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1
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Xu R, Wang C, Cong H, Wang L. Association of metabolic phenotypes with cardiovascular events in patients aged 18-45 with acute coronary syndrome. Endocrine 2025; 88:457-466. [PMID: 39930111 DOI: 10.1007/s12020-025-04169-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 01/14/2025] [Indexed: 05/13/2025]
Abstract
BACKGROUND Obesity and metabolic syndrome are related to cardiovascular events. However, the association different metabolic phenotypes and obesity with cardiovascular events among young adults aged 18-45 with acute coronary syndrome (ACS) remains unclear. The study aimed to investigate the prognosis of patients aged 18-45 years with ACS based on their metabolic phenotype. METHODS This study included 1787 patients with ACS ≤ 45 years of age who underwent coronary angiography. Patients were divided into four groups according to metabolic phenotype: metabolically healthy non-obesity (MHN); MHO; metabolically unhealthy non-obesity (MUN); and metabolically unhealthy obesity (MUO). The primary outcome was major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke, or unplanned revascularization. RESULTS Among 1787 patients with ACS, the median age was 41.6 years, 1675 (93.7%) were men, 1111 (62.2%) had obesity, and 659 (36.9%) were classified as MHO. During a median 65 months follow-up, 404 MACE occurred. Multivariate analysis showed that MHO was correlated with a decreased risk of MACE, while MUN significantly increased the risk compared to MHN (MHO: HR 0.69, 95%CI 0.52-0.92, P = 0.011; MUN: HR 1.47, 95%CI 1.07-2.02 P = 0.018). Moreover, restricted cubic spline analysis revealed a linear relationship between body mass index (BMI) and the incidence of MACE (Pnonlinear = 0.304, Poverall < 0.001). CONCLUSIONS MHO was correlated with a decreased risk of MACE, while MUN significantly increased the risk compared to MHN. Moreover, there was a linear relationship between BMI and the incidence of MACE.
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Affiliation(s)
- Rongdi Xu
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Chen Wang
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
| | - Hongliang Cong
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China.
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin Chest Hospital, Tianjin, China.
| | - Le Wang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin Chest Hospital, Tianjin, China.
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2
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Tian J, Dong Y, Xu Z, Ke J, Xu H. Association between triglyceride glucose-body mass index and 365-day mortality in patients with critical coronary heart disease. Front Endocrinol (Lausanne) 2025; 16:1513898. [PMID: 40255500 PMCID: PMC12006011 DOI: 10.3389/fendo.2025.1513898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/17/2025] [Indexed: 04/22/2025] Open
Abstract
Objectives The aim of this study was to analyze the association between TyG-BMI and 365-day mortality in critically ill patients with CHD. Methods Patient data were extracted from the MIMIC-IV database. All patients were categorized into 3 groups based on TyG-BMI index: Low TyG-BMI index group, Medium TyG-BMI index group, and High TyG-BMI index group. Outcomes included primary and secondary outcomes, with the primary outcome being 365-day mortality and the secondary outcomes being hospital survival, intensive care unit (ICU) survival, and 28-day, 90-day, and 180-day mortality. The Kaplan-Meier survival curves were used to compare the outcomes of the three groups. The relationship between TyG-BMI index and 365-day mortality was assessed using multivariate Cox proportional risk regression models and restricted cubic spline curves (RCS). Results 889 critically ill patients with CHD were analyzed. Among them, 600 (67.50%) were male patients with a mean age of 68.37 years and 289 (32.50%) were female patients with a mean age of 73.91 years. Patients with a medium TyG-BMI index had the best 365-day prognostic outcome and the highest survival rate compared with patients in the Low and High TyG-BMI index groups [201 (67.68%) vs. 166 (56.08%), 188 (63.51%); P=0.013]. After fully adjusted modeling analysis, the hazard ratio (HR) for 365-day mortality was found to be 0.71 (95% CI 0.54-0.93, P=0.012) for the Medium TyG-BMI index group. Meanwhile, RCS analysis showed an L-shaped relationship between TyG-BMI index and 365-day mortality. Conclusions The TyG-BMI index is significantly associated with 365-day mortality in patients with severe CHD.
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Affiliation(s)
| | | | | | | | - Hongyang Xu
- Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of
Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China
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3
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Jawla N, Kar R, Patil VS, Arimbasseri GA. Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics. Immunology 2025; 174:73-91. [PMID: 39263985 DOI: 10.1111/imm.13860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 08/13/2024] [Indexed: 09/13/2024] Open
Abstract
Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.
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Affiliation(s)
- Neha Jawla
- Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
| | - Raunak Kar
- Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
| | - Veena S Patil
- Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
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4
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Kokabeh F, Bahadoran Z, Mahdavi M, Valizadeh M, Barzin M, Azizi F, Hosseinpanah F. The association of obesity phenotypes and risk of cardiovascular disease using time-varying and time-invariant approaches: An 18-year follow-up cohort study. Nutr Metab Cardiovasc Dis 2025; 35:103755. [PMID: 39448315 DOI: 10.1016/j.numecd.2024.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND AND AIM Our aim was risk estimation for cardiovascular disease (CVD) across obesity phenotypes over 18 years of follow-up using both time-invariant and time-varying approaches. METHODS AND RESULTS This prospective cohort study included 9752 participants aged ≥30 years examined in the first and second phases of the Tehran Lipid and Glucose Study (1999-2001 and 2002-2005). Six phenotypes [i.e., metabolically healthy normal weight (MHNW), overweight (MHOW), and obese (MHO), as well as metabolically unhealthy normal weight (MUNW), overweight (MUOW), and obese (MUO)] were defined based on the body mass index (BMI) and metabolic status. Incident CVD was documented until March 2018. Time-invariant and time-varying Cox regression models were used to estimate CVD hazard ratio (HRs) for obesity phenotypes. Mean age of the participants was 46.6 ± 12.0 years, and 53.9 % of them were women. During 18 years of follow-up, 1083 new CVD events occurred. In metabolically unhealthy individuals, but not metabolically healthy people, multivariable-adjusted HRs for CVD events increased by BMI according to time-varying (HR = 1.6, 95 % CI = 1.13-2.26 for MUNW; HR = 1.92, 95 % CI = 1.43-2.58 for MUOW; HR = 1.94, 95 % CI = 1.4-2.68 for MUO) and time-invariant (HR = 1.85, 95 % CI = 1.01-3.39 for MUNW; HR = 2.75, 95 % CI = 1.63-4.63 for MUOW, and HR = 3.26, 95 % CI = 1.95-5.47 for MUO) models. CONCLUSION Metabolically unhealthy overweight and obese individuals are at increased risk of CVD and should be regularly screened to prevent possible cardiovascular events.
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Affiliation(s)
- Fatemeh Kokabeh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Bahadoran
- Micronutrient Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Mahdavi
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Majid Valizadeh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Barzin
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farhad Hosseinpanah
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Lietzén MS, Mari A, Ojala R, Hentilä J, Koskensalo K, Lautamäki R, Löyttyniemi E, Parkkola R, Saunavaara V, Kirjavainen AK, Rajander J, Malm T, Lahti L, Rinne JO, Pietiläinen KH, Iozzo P, Hannukainen JC. Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI. Biomolecules 2024; 14:1070. [PMID: 39334836 PMCID: PMC11430379 DOI: 10.3390/biom14091070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/23/2024] [Accepted: 08/25/2024] [Indexed: 09/30/2024] Open
Abstract
Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [18F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins (p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins (p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.
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Affiliation(s)
| | - Andrea Mari
- Institute of Neuroscience, National Research Council (CNR), 35128 Padua, Italy
| | - Ronja Ojala
- Turku PET Centre, University of Turku, 20521 Turku, Finland
| | - Jaakko Hentilä
- Turku PET Centre, University of Turku, 20521 Turku, Finland
| | - Kalle Koskensalo
- Department of Medical Physics, Turku University Hospital, 20520 Turku, Finland
| | | | | | - Riitta Parkkola
- Department of Radiology, Turku University Hospital and University of Turku, 20520 Turku, Finland
| | - Virva Saunavaara
- Turku PET Centre, University of Turku, 20521 Turku, Finland
- Department of Medical Physics, Turku University Hospital, 20520 Turku, Finland
| | - Anna K Kirjavainen
- Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, 20521 Turku, Finland
| | - Johan Rajander
- Turku PET Centre, Accelerator Laboratory, Åbo Akademi University, 20500 Turku, Finland
| | - Tarja Malm
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland
| | - Leo Lahti
- Department of Computing, University of Turku, 20521 Turku, Finland
| | - Juha O Rinne
- Turku PET Centre, University of Turku, 20521 Turku, Finland
- Turku PET Centre, Turku University Hospital, 20520 Turku, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
- Abdominal Center, Obesity Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, 00014 Helsinki, Finland
| | - Patricia Iozzo
- Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy
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Gjela M, Askeland A, Mellergaard M, Drewes AM, Handberg A, Frøkjær JB. Intra-pancreatic fat deposition and its relation to obesity: a magnetic resonance imaging study. Scand J Gastroenterol 2024; 59:742-748. [PMID: 38557425 DOI: 10.1080/00365521.2024.2333365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/19/2024] [Accepted: 03/17/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVES Intra-pancreatic fat deposition (IPFD) is suspected to be associated with various medical conditions. This study aimed to assess pancreatic fat content in lean and obese individuals, characterize obese individuals with and without IPFD, and explore the underlying mechanisms. MATERIALS AND METHODS Sixty-two obese individuals without diabetes and 35 lean controls underwent magnetic resonance imaging (MRI) using proton density fat fraction (PDFF) maps to evaluate pancreatic and hepatic fat content, and visceral adipose tissue (VAT) content. Pancreatic fibrosis was explored by T1 relaxation time and MR elastography (MRE) measurements. Associations between pancreatic fat, measures of obesity and metabolic syndrome were examined using uni- and multivariate regression analyses. RESULTS Pancreatic PDFF was higher in obese than in lean controls (median 8.0%, interquartile range (6.1;13.3) % vs 2.6(1.7;3.9)%, p < 0.001). Obese individuals with IPFD (PDFF ≥6.2%) had higher waist circumference (114.0 ± 12.5 cm vs 105.2 ± 8.7 cm, p = 0.007) and VAT (224.9(142.1; 316.1) cm2 vs 168.2(103.4; 195.3) cm2, p < 0.001) than those without. In univariate analysis, pancreatic PDFF in obese individuals correlated with BMI (r = 0.27, p = 0.03), waist circumference (r = 0.44, p < 0.001), VAT (r = 0.37, p = 0.004), hepatic PDFF (r = 0.25, p = 0.046) and diastolic blood pressure (r = 0.32, p = 0.01). However, in multivariate analysis, only VAT was associated to pancreatic fat content. MRI measures of pancreatic fibrosis indicated no evident fibrosis in relation to increased pancreatic fat content. CONCLUSIONS Pancreatic fat content was increased in obese individuals compared with lean controls and predominantly correlated with the amount of visceral adipose tissue. Pancreatic fat content was not clearly linked to measures of pancreatic fibrosis.
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Affiliation(s)
- Mimoza Gjela
- Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Anders Askeland
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Maiken Mellergaard
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jens Brøndum Frøkjær
- Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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7
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Ramos RS, Rocco IS, Viceconte M, Santo JADE, Berwanger O, Santos RHN, Kalil RAK, Jatene FB, Cavalcanti AB, Zilli AC, Pimentel WDS, Hossne Junior NA, Branco JNR, Trimer R, Evora PRB, Gomes WJ, Guizilin S. Association Between Body Mass Index, Obesity, and Clinical Outcomes Following Coronary Artery Bypass Grafting in Brazil: An Analysis of One Year of Follow-up of BYPASS Registry Patients. Braz J Cardiovasc Surg 2024; 39:e20230133. [PMID: 38569010 PMCID: PMC10987126 DOI: 10.21470/1678-9741-2023-0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/05/2024] Open
Abstract
OBJECTIVE To investigate the association between body mass index (BMI), obesity, clinical outcomes, and mortality following coronary artery bypass grafting (CABG) in Brazil using a large sample with one year of follow-up from the Brazilian Registry of Cardiovascular Surgeries in Adults (or BYPASS) Registry database. METHODS A multicenter cohort-study enrolled 2,589 patients submitted to isolated CABG and divided them into normal weight (BMI 20.0-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obesity (BMI > 30.0 kg/m2) groups. Inpatient postoperative outcomes included the most frequently described complications and events. Collected post-discharge outcomes included rehospitalization and mortality rates within 30 days, six months, and one year of follow-up. RESULTS Sternal wound infections (SWI) rate was higher in obese compared to normal-weight patients (relative risk [RR]=5.89, 95% confidence interval [CI]=2.37-17.82; P=0.001). Rehospitalization rates in six months after discharge were higher in obesity and overweight groups than in normal weight group (χ=6.03, P=0.049); obese patients presented a 2.2-fold increase in the risk for rehospitalization within six months compared to normal-weight patients (RR=2.16, 95% CI=1.17-4.09; P=0.045). Postoperative complications and mortality rates did not differ among groups during time periods. CONCLUSION Obesity increased the risk for SWI, leading to higher rehospitalization rates and need for surgical interventions within six months following CABG. Age, female sex, and diabetes were associated with a higher risk of mortality. The obesity paradox remains controversial since BMI may not be sufficient to assess postoperative risk in light of more complex and dynamic evaluations of body composition and physical fitness.
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Affiliation(s)
- Rodrigo Santin Ramos
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Isadora Salvador Rocco
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Marcela Viceconte
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | | | - Otavio Berwanger
- Instituto de Pesquisa - IP, Hospital do Coração -
HCor, São Paulo, São Paulo, Brazil
| | | | - Renato Abdala Karam Kalil
- Instituto de Cardiologia do Rio Grande do Sul,
Fundação Universitária de Cardiologia, Porto Alegre, Rio Grande
do Sul, Brazil
| | - Fabio B. Jatene
- Instituto de Pesquisa - IP, Hospital do Coração -
HCor, São Paulo, São Paulo, Brazil
- Cardiovascular Surgery Division, Instituto do Coração
- InCor, Hospital das Clínicas da Faculdade de Medicina da Universidade de
São Paulo - HCFMUSP, São Paulo, São Paulo, Brazil
| | | | - Alexandre Cabral Zilli
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Walace de Souza Pimentel
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Nelson Américo Hossne Junior
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - João Nelson Rodrigues Branco
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Renata Trimer
- Department of Physical Therapy, Universidade Federal de São
Carlos, São Carlos, São Paulo, Brazil
| | - Paulo Roberto Barbora Evora
- Department of Surgery and Anatomy, Escola de Medicina de
Riberão Preto, Universidade de São Paulo, Ribeirão Preto,
São Paulo, Brazil
| | - Walter J. Gomes
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Solange Guizilin
- Cardiology Postgraduate Program, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
- Cardiovascular Surgery Discipline, Escola Paulista de Medicina,
Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
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8
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Baichuan Y, Gomes Reis M, Tavakoli S, Khodadadi N, Sohouli MH, Sernizon Guimarães N. The effects of NAD+ precursor (nicotinic acid and nicotinamide) supplementation on weight loss and related hormones: a systematic review and meta-regression analysis of randomized controlled trials. Front Nutr 2023; 10:1208734. [PMID: 37854354 PMCID: PMC10579603 DOI: 10.3389/fnut.2023.1208734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/18/2023] [Indexed: 10/20/2023] Open
Abstract
Background Despite the fact that obesity and overweight are serious major health problems worldwide, fighting against them is also considered a challenging issue. Several interventional studies have evaluated the potential weight-reduction effect of nicotinamide adenine dinucleotide (NAD+) precursor. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of NAD+ precursor supplementation on weight loss, adiponectin, and leptin. Methods Scopus, PubMed/Medline, Web of Science, Cochrane, and Embase databases were searched using standard keywords to identify all controlled trials investigating the weight loss and related hormones effects of NAD+ precursor. Pooled weighted mean difference and 95% confidence intervals were achieved by random-effects model analysis for the best estimation of outcomes. Results Twenty two treatment arms with 5,144 participants' were included in this systematic review and meta-regression analysis. The pooled findings showed that NAD+ precursor supplementation has an effect on lowering BMI (weighted mean difference (WMD): -0.19 kg/m2, 95% confidence interval (CI): -0.29 to -0.09, p < 0.001) and increasing adiponectin (WMD: 1.59 μg/mL, 95% CI: 0.49 to 2.68, p = 0.004) in humans compared with control groups. However, no significant effect was observed on body weight and leptin. There was a significant relationship between doses of intervention with changes in BMI. In addition, subgroup analysis showed that BMI reduction was greater when receiving nicotinic acid (NA) supplementation than nicotinamide (NE) supplementation. Conclusion NAD+ precursor had significant effects on weight management with the reduction of BMI and increasing adiponectin.
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Affiliation(s)
- You Baichuan
- SDU-ANU Joint Science College, Shandong University, Weihai, China
| | - Marcela Gomes Reis
- Master in Health Science at Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- OPENS: Observatory of Epidemiology, Nutrition and Health Research, Faculdade Ciências Médicas de Minas Gerais/FELUMA, Belo Horizonte, Minas Gerais, Brazil
| | - Sogand Tavakoli
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navideh Khodadadi
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nathalia Sernizon Guimarães
- OPENS: Observatory of Epidemiology, Nutrition and Health Research, Faculdade Ciências Médicas de Minas Gerais/FELUMA, Belo Horizonte, Minas Gerais, Brazil
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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9
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Preda A, Carbone F, Tirandi A, Montecucco F, Liberale L. Obesity phenotypes and cardiovascular risk: From pathophysiology to clinical management. Rev Endocr Metab Disord 2023; 24:901-919. [PMID: 37358728 PMCID: PMC10492705 DOI: 10.1007/s11154-023-09813-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/31/2023] [Indexed: 06/27/2023]
Abstract
Obesity epidemic reached the dimensions of a real global health crisis with more than one billion people worldwide living with obesity. Multiple obesity-related mechanisms cause structural, functional, humoral, and hemodynamic alterations with cardiovascular (CV) deleterious effects. A correct assessment of the cardiovascular risk in people with obesity is critical for reducing mortality and preserving quality of life. The correct identification of the obesity status remains difficult as recent evidence suggest that different phenotypes of obesity exist, each one associated with different degrees of CV risk. Diagnosis of obesity cannot depend only on anthropometric parameters but should include a precise assessment of the metabolic status. Recently, the World Heart Federation and World Obesity Federation provided an action plan for management of obesity-related CV risk and mortality, stressing for the instauration of comprehensive structured programs encompassing multidisciplinary teams. In this review we aim at providing an updated summary regarding the different obesity phenotypes, their specific effects on CV risk and differences in clinical management.
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Affiliation(s)
| | - Federico Carbone
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy
| | - Amedeo Tirandi
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy
| | - Fabrizio Montecucco
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.
- Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy.
| | - Luca Liberale
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132, Genoa, Italy
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10
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Longo M, Zatterale F, Spinelli R, Naderi J, Parrillo L, Florese P, Nigro C, Leone A, Moccia A, Desiderio A, Raciti GA, Miele C, Smith U, Beguinot F. Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics. Clin Epigenetics 2023; 15:144. [PMID: 37679776 PMCID: PMC10486065 DOI: 10.1186/s13148-023-01556-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/14/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR. RESULTS Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression. CONCLUSIONS Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
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Affiliation(s)
- Michele Longo
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Federica Zatterale
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Rosa Spinelli
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Jamal Naderi
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Luca Parrillo
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Pasqualina Florese
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Cecilia Nigro
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Alessia Leone
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Augusta Moccia
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Antonella Desiderio
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Gregory A Raciti
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.
| | - Claudia Miele
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Ulf Smith
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Francesco Beguinot
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.
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11
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Garske KM, Kar A, Comenho C, Balliu B, Pan DZ, Bhagat YV, Rosenberg G, Koka A, Das SS, Miao Z, Sinsheimer JS, Kaprio J, Pietiläinen KH, Pajukanta P. Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes. Nat Commun 2023; 14:4214. [PMID: 37452040 PMCID: PMC10349101 DOI: 10.1038/s41467-023-39919-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 07/04/2023] [Indexed: 07/18/2023] Open
Abstract
Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions.
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Affiliation(s)
- Kristina M Garske
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Asha Kar
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Caroline Comenho
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Brunilda Balliu
- Department of Computational Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - David Z Pan
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA
| | - Yash V Bhagat
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Gregory Rosenberg
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Amogha Koka
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Sankha Subhra Das
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Zong Miao
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA
| | - Janet S Sinsheimer
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Department of Computational Medicine, UCLA, Los Angeles, CA, 90095, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, 90095, USA
| | - Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland
- Obesity Center, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, 00014, Finland
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
- Department of Computational Medicine, UCLA, Los Angeles, CA, 90095, USA.
- Institute for Precision Heath, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
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12
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Ruggiero AD, Vemuri R, Block M, DeStephanis D, Davis M, Chou J, Williams A, Brock A, Das SK, Kavanagh K. Macrophage Phenotypes and Gene Expression Patterns Are Unique in Naturally Occurring Metabolically Healthy Obesity. Int J Mol Sci 2022; 23:12680. [PMID: 36293536 PMCID: PMC9604193 DOI: 10.3390/ijms232012680] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022] Open
Abstract
Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers of these phenotypes, a 44-animal African green monkey cohort was selected using metabolic syndrome risk criteria to represent these four clinically defined health groups. Body composition imaging and subcutaneous adipose tissue (SQ AT) biopsies were collected. Differences in adipocyte size, macrophage subtype distribution, gene expression, vascularity and fibrosis were analyzed using digital immunohistopathology, unbiased RNA-seq, endothelial CD31, and Masson’s trichrome staining, respectively. MHO AT demonstrated significant increases in M2 macrophages (p = 0.02) and upregulation of fatty acid oxidation-related terms and transcripts, including FABP7 (p = 0.01). MUO AT demonstrated downregulation of these factors and co-occurring upregulation of immune responses. These changes occurred without differences in AT distributions, adipocyte size, AT endothelial cells, collagen I deposition, or circulating cytokine levels. Without unhealthy diet consumption, healthy obesity is defined by an increased SQ AT M2/M1 macrophage ratio and lipid handling gene expression. We highlight M2 macrophages and fatty acid oxidation as targets for improving metabolic health with obesity.
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Affiliation(s)
- Alistaire D. Ruggiero
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Ravichandra Vemuri
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Masha Block
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Darla DeStephanis
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Matthew Davis
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Jeff Chou
- Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Abigail Williams
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Ashlynn Brock
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Swapan Kumar Das
- Department of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Kylie Kavanagh
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- College of Health and Medicine, University of Tasmania, Hobart 7000, Australia
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13
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Lundgren S, Kuitunen S, Pietiläinen KH, Hurme M, Kähönen M, Männistö S, Perola M, Lehtimäki T, Raitakari O, Kaprio J, Ollikainen M. BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for body mass index. J Intern Med 2022; 292:627-640. [PMID: 35699258 PMCID: PMC9540898 DOI: 10.1111/joim.13528] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Obesity is a heritable complex phenotype that can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various "epigenetic clocks." Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely correlates with mortality. OBJECTIVES We aimed to assess the cross-sectional association of body mass index (BMI) with age acceleration in twins to limit confounding by genetics and shared environment. METHODS AND RESULTS Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twin pairs, and DNAm was measured using the Illumina 450K array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10-12 ) per one-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI >3 kg/m2 ) had an epigenetic age 5.2 months older than their lighter cotwin (p-value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 4.1 × 10-25 ) from adjusted models. CONCLUSION We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.
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Affiliation(s)
- Sara Lundgren
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Sara Kuitunen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Obesity Center, Endocrinology, Abdominal Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Mikko Hurme
- Department of Microbiology and Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.,Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Satu Männistö
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Markus Perola
- Finnish Institute for Health and Welfare, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Olli Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.,Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.,Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Miina Ollikainen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
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14
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Chen YC, Li WC, Ke PH, Chen IC, Yu W, Huang HY, Xiong XJ, Chen JY. Association between metabolic body composition status and vitamin D deficiency: A cross-sectional study. Front Nutr 2022; 9:940183. [PMID: 35967768 PMCID: PMC9365955 DOI: 10.3389/fnut.2022.940183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
This study aimed to investigate the risk of vitamin D deficiency in a relatively healthy Asian population, with (i) metabolically healthy normal weight (MHNW) (homeostasis model assessment-insulin resistance [HOMA-IR] < 2. 5 without metabolic syndrome [MS], body mass index [BMI] < 25), (ii) metabolically healthy obesity (MHO) (HOMA-IR < 2.5, without MS, BMI ≥ 25), (iii) metabolically unhealthy normal weight (MUNW) (HOMA-IR ≥ 2.5, or with MS, BMI < 25), and (iv) metabolically unhealthy obesity (MUO) (HOMA-IR ≥ 2.5, or with MS, BMI ≥ 25) stratified by age and sex. This cross-sectional study involved 6,655 participants aged ≥ 18 years who underwent health checkups between 2013 and 2016 at the Chang Gung Memorial Hospital. Cardiometabolic and inflammatory markers including anthropometric variables, glycemic indices, lipid profiles, high-sensitivity C-reactive protein (hs-CRP), and serum 25-hydroxy vitamin D levels, were retrospectively investigated. Compared to the MHNW group, the MHO group showed a higher odds ratio (OR) [1.35, 95% confidence interval (CI) 1.05-1.73] for vitamin D deficiency in men aged < 50 years. By contrast, in men aged > 50 years, the risk of vitamin D deficiency was higher in the MUO group (OR 1.44, 95% CI 1.05-1.97). Among women aged < and ≥ 50 years, the MUO group demonstrated the highest risk for vitamin D deficiency, OR 2.33 vs. 1.54, respectively. Our study revealed that in women of all ages and men aged > 50 years, MUO is associated with vitamin D deficiency and elevated levels of metabolic biomarkers. Among men aged < 50 years, MHO had the highest OR for vitamin D deficiency.
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Affiliation(s)
- Yi-Chuan Chen
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Wen-Cheng Li
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan.,Department of Health Management, Xiamen Chang Gung Hospital Hua Qiao University, Xiamen, China
| | - Pin-Hsuan Ke
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - I-Chun Chen
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Wei Yu
- Department of Health Management, Xiamen Chang Gung Hospital Hua Qiao University, Xiamen, China
| | - Hsiung-Ying Huang
- Department of Pulmonary and Critical Care Medicine, Xiamen Chang Gung Hospital Hua Qiao University, Xiamen, China
| | - Xue-Jie Xiong
- Department of Oncology, Xiamen Chang Gung Hospital Hua Qiao University, Xiamen, China
| | - Jau-Yuan Chen
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
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15
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Orozco-Ruiz X, Anesi A, Mattivi F, Breteler MMB. Branched-Chain and Aromatic Amino Acids Related to Visceral Adipose Tissue Impact Metabolic Health Risk Markers. J Clin Endocrinol Metab 2022; 107:e2896-e2905. [PMID: 35325166 DOI: 10.1210/clinem/dgac160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Visceral (VAT) and subcutaneous adipose tissue (SAT) function as endocrine organs capable of influencing metabolic health across adiposity levels. OBJECTIVE We aimed to investigate whether metabolites associated with VAT and SAT impact metabolic health through metabolite concentrations. METHODS Analyses are based on 1790 participants from the population-based Rhineland Study. We assessed plasma levels of methionine (Met), branched-chain amino acids (BCAA), aromatic amino acids (AAA), and their metabolic downstream metabolites with liquid chromatography-mass spectrometry. VAT and SAT volumes were assessed by magnetic resonance imaging (MRI). Metabolically healthy and unhealthy phenotypes were defined using Wildman criteria. RESULTS Metabolically unhealthy participants had higher concentrations of BCAA than metabolically healthy participants (P < 0.001). In metabolically unhealthy participants, VAT volumes were significantly associated with levels of L-isoleucine, L-leucine, indole-3-lactic acid, and indole-3-propionic acid (in log SD units: β = 0.16, P = 0.003; β = 0.12, P = 0.038; β = 0.11, P = 0.035 and β = -0.16, P = 0.010, respectively). Higher concentrations of certain BCAA and AAA-downstream metabolites significantly increased the odds of cardiometabolic risk markers. The relation between VAT volume and cardiometabolic risk markers was mediated by BCAA (indirect effects 3.7%-11%, P = 0.02 to < 0.0001), while the effect of VAT on systemic inflammation was mediated through higher kynurenine concentrations (indirect effect 6.4%, P < 0.0001). CONCLUSION Larger volumes of VAT in metabolically unhealthy individuals are associated with altered concentrations of circulating BCAA and AAA-downstream metabolites, increasing the odds of cardiometabolic risk markers. This suggests that these metabolites are involved in the mechanisms that underlie the relationship of abdominal VAT with metabolic health.
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Affiliation(s)
- Ximena Orozco-Ruiz
- Population Health Sciences, German Center for Neurodegenerative diseases (DZNE), 53127 Bonn, Germany
| | - Andrea Anesi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), 38010 San Michele all'Adige, Italy
| | - Fulvio Mattivi
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach (FEM), 38010 San Michele all'Adige, Italy
- University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), 38123 Povo, Italy
| | - Monique M B Breteler
- Population Health Sciences, German Center for Neurodegenerative diseases (DZNE), 53127 Bonn, Germany
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, 53127 Bonn, Germany
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16
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Mikłosz A, Nikitiuk BE, Chabowski A. Using adipose-derived mesenchymal stem cells to fight the metabolic complications of obesity: Where do we stand? Obes Rev 2022; 23:e13413. [PMID: 34985174 PMCID: PMC9285813 DOI: 10.1111/obr.13413] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022]
Abstract
Obesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell-based therapies have become a promising tool for therapeutic intervention. Among them are adipose-derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro-inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | | | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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17
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Matrisome alterations in obesity – Adipose tissue transcriptome study on monozygotic weight-discordant twins. Matrix Biol 2022; 108:1-19. [DOI: 10.1016/j.matbio.2022.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 02/16/2022] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
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18
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Gander J, Carrard J, Gallart-Ayala H, Borreggine R, Teav T, Infanger D, Colledge F, Streese L, Wagner J, Klenk C, Nève G, Knaier R, Hanssen H, Schmidt-Trucksäss A, Ivanisevic J. Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights. Front Cardiovasc Med 2021; 8:792350. [PMID: 34977199 PMCID: PMC8716394 DOI: 10.3389/fcvm.2021.792350] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 11/09/2021] [Indexed: 12/26/2022] Open
Abstract
Coronary artery disease (CAD) remains the leading cause of death worldwide. Expanding patients' metabolic phenotyping beyond clinical chemistry investigations could lead to earlier recognition of disease onset and better prevention strategies. Additionally, metabolic phenotyping, at the molecular species level, contributes to unravel the roles of metabolites in disease development. In this cross-sectional study, we investigated clinically healthy individuals (n = 116, 65% male, 70.8 ± 8.7 years) and patients with CAD (n = 54, 91% male, 67.0 ± 11.5 years) of the COmPLETE study. We applied a high-coverage quantitative liquid chromatography-mass spectrometry approach to acquire a comprehensive profile of serum acylcarnitines, free carnitine and branched-chain amino acids (BCAAs), as markers of mitochondrial health and energy homeostasis. Multivariable linear regression analyses, adjusted for confounders, were conducted to assess associations between metabolites and CAD phenotype. In total, 20 short-, medium- and long-chain acylcarnitine species, along with L-carnitine, valine and isoleucine were found to be significantly (adjusted p ≤ 0.05) and positively associated with CAD. For 17 acylcarnitine species, associations became stronger as the number of affected coronary arteries increased. This implies that circulating acylcarnitine levels reflect CAD severity and might play a role in future patients' stratification strategies. Altogether, CAD is characterized by elevated serum acylcarnitine and BCAA levels, which indicates mitochondrial imbalance between fatty acid and glucose oxidation.
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Affiliation(s)
- Joséphine Gander
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Justin Carrard
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Hector Gallart-Ayala
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Rébecca Borreggine
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Tony Teav
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Denis Infanger
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Flora Colledge
- Division of Sports Science, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Lukas Streese
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Jonathan Wagner
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Christopher Klenk
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Gilles Nève
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Raphael Knaier
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Henner Hanssen
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
| | - Arno Schmidt-Trucksäss
- Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland
- Arno Schmidt-Trucksäss
| | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- *Correspondence: Julijana Ivanisevic
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19
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Bean C, Audano M, Varanita T, Favaretto F, Medaglia M, Gerdol M, Pernas L, Stasi F, Giacomello M, Herkenne S, Muniandy M, Heinonen S, Cazaly E, Ollikainen M, Milan G, Pallavicini A, Pietiläinen KH, Vettor R, Mitro N, Scorrano L. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. Nat Metab 2021; 3:1633-1647. [PMID: 34873337 DOI: 10.1038/s42255-021-00497-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/27/2021] [Indexed: 12/14/2022]
Abstract
White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.
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Affiliation(s)
- Camilla Bean
- Department of Biology, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Matteo Audano
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Tatiana Varanita
- Department of Biology, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | | | - Marta Medaglia
- Department of Biology, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Marco Gerdol
- Department of Life Science, University of Trieste, Trieste, Italy
| | - Lena Pernas
- Department of Biology, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Fabio Stasi
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Stèphanie Herkenne
- Department of Biology, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Maheswary Muniandy
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Sini Heinonen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Emma Cazaly
- Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Miina Ollikainen
- Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | | | | | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Obesity Centre, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Roberto Vettor
- Department of Medicine, University of Padova, Padova, Italy
| | - Nico Mitro
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Luca Scorrano
- Department of Biology, University of Padova, Padova, Italy.
- Veneto Institute of Molecular Medicine, Padova, Italy.
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20
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Mitochondria and Antibiotics: For Good or for Evil? Biomolecules 2021; 11:biom11071050. [PMID: 34356674 PMCID: PMC8301944 DOI: 10.3390/biom11071050] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 01/16/2023] Open
Abstract
The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.
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21
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Kalafati M, Lenz M, Ertaylan G, Arts ICW, Evelo CT, van Greevenbroek MMJ, Blaak EE, Adriaens M, Kutmon M. Assessing the Contribution of Relative Macrophage Frequencies to Subcutaneous Adipose Tissue. Front Nutr 2021; 8:675935. [PMID: 34136521 PMCID: PMC8200404 DOI: 10.3389/fnut.2021.675935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/16/2021] [Indexed: 01/09/2023] Open
Abstract
Background: Macrophages play an important role in regulating adipose tissue function, while their frequencies in adipose tissue vary between individuals. Adipose tissue infiltration by high frequencies of macrophages has been linked to changes in adipokine levels and low-grade inflammation, frequently associated with the progression of obesity. The objective of this project was to assess the contribution of relative macrophage frequencies to the overall subcutaneous adipose tissue gene expression using publicly available datasets. Methods: Seven publicly available microarray gene expression datasets from human subcutaneous adipose tissue biopsies (n = 519) were used together with TissueDecoder to determine the adipose tissue cell-type composition of each sample. We divided the subjects in four groups based on their relative macrophage frequencies. Differential gene expression analysis between the high and low relative macrophage frequencies groups was performed, adjusting for sex and study. Finally, biological processes were identified using pathway enrichment and network analysis. Results: We observed lower frequencies of adipocytes and higher frequencies of adipose stem cells in individuals characterized by high macrophage frequencies. We additionally studied whether, within subcutaneous adipose tissue, interindividual differences in the relative frequencies of macrophages were reflected in transcriptional differences in metabolic and inflammatory pathways. Adipose tissue of individuals with high macrophage frequencies had a higher expression of genes involved in complement activation, chemotaxis, focal adhesion, and oxidative stress. Similarly, we observed a lower expression of genes involved in lipid metabolism, fatty acid synthesis, and oxidation and mitochondrial respiration. Conclusion: We present an approach that combines publicly available subcutaneous adipose tissue gene expression datasets with a deconvolution algorithm to calculate subcutaneous adipose tissue cell-type composition. The results showed the expected increased inflammation gene expression profile accompanied by decreased gene expression in pathways related to lipid metabolism and mitochondrial respiration in subcutaneous adipose tissue in individuals characterized by high macrophage frequencies. This approach demonstrates the hidden strength of reusing publicly available data to gain cell-type-specific insights into adipose tissue function.
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Affiliation(s)
- Marianthi Kalafati
- Deparment of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Michael Lenz
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands.,Institute of Organismic and Molecular Evolution, Johannes Gutenberg University of Mainz, Mainz, Germany.,Preventive Cardiology and Preventive Medicine-Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Gökhan Ertaylan
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands.,Unit Health, Flemish Institute for Technological Research, Antwerp, Belgium
| | - Ilja C W Arts
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands.,Department of Epidemiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Chris T Evelo
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands.,Department of Bioinformatics-BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Marleen M J van Greevenbroek
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Ellen E Blaak
- Deparment of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Michiel Adriaens
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands
| | - Martina Kutmon
- Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands.,Department of Bioinformatics-BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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22
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Plaza-Florido A, Altmäe S, Esteban FJ, Cadenas-Sanchez C, Aguilera CM, Einarsdottir E, Katayama S, Krjutškov K, Kere J, Zaldivar F, Radom-Aizik S, Ortega FB. Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity. Pediatr Res 2021; 89:1687-1694. [PMID: 33230195 DOI: 10.1038/s41390-020-01276-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/18/2020] [Accepted: 10/27/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes. The underlying mechanisms for those differences are still unclear. This study aimed to analyze the whole-blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. METHODS Twenty-seven children with OW/OB (10.1 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein-cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers were additionally determined. Total blood RNA was analyzed by 5'-end RNA-sequencing. RESULTS Whole-blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. Thirty-two genes differentially expressed were linked to metabolism, mitochondrial, and immune functions. CONCLUSIONS The identified gene expression patterns related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity. IMPACT A distinct pattern of whole-blood transcriptome profile (RNA-seq) was identified in children with metabolic healthy overweight/obesity (MHO) compared to metabolic unhealthy overweight/obesity (MUO) phenotype. The most relevant genes in understanding the molecular basis underlying the MHO/MUO phenotypes in children could be: RREB1, FAM83E, SLC44A1, NRG1, TMC5, CYP3A5, TRIM11, and ADAMTSL2. The identified whole-blood transcriptome profile related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity.
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Affiliation(s)
- Abel Plaza-Florido
- PROFITH "PROmoting FITness and Health Through Physical Activity" Research Group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, 18011, Granada, Spain.
| | - Signe Altmäe
- Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Granada, Granada, Spain.,Competence Centre on Health Technologies, Tartu, Estonia.,Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
| | - Francisco J Esteban
- Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaen, Jaen, Spain
| | - Cristina Cadenas-Sanchez
- PROFITH "PROmoting FITness and Health Through Physical Activity" Research Group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, 18011, Granada, Spain.,Institute for Innovation & Sustainable Development in Food Chain (IS-FOOD), Public University of Navarra, Pamplona, Spain
| | - Concepción M Aguilera
- Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.,Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Centre for Biomedical Research, University of Granada, Granada, Spain.,CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain
| | - Elisabet Einarsdottir
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, SE-171 21, Solna, Sweden
| | - Shintaro Katayama
- Stem Cells and Metabolism Research Program (STEMM), University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Kaarel Krjutškov
- Competence Centre on Health Technologies, Tartu, Estonia.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.,Institute of Clinical Medicine, Department of Obstetrics and Gynecology, University of Tartu, Tartu, Estonia
| | - Juha Kere
- Stem Cells and Metabolism Research Program (STEMM), University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Frank Zaldivar
- Pediatric Exercise and Genomics Research Center, UC Irvine School of Medicine, Irvine, CA, USA
| | - Shlomit Radom-Aizik
- Pediatric Exercise and Genomics Research Center, UC Irvine School of Medicine, Irvine, CA, USA
| | - Francisco B Ortega
- PROFITH "PROmoting FITness and Health Through Physical Activity" Research Group, Sport and Health University Research Institute (iMUDS), Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, 18011, Granada, Spain.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
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24
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van der Kolk BW, Muniandy M, Kaminska D, Alvarez M, Ko A, Miao Z, Valsesia A, Langin D, Vaittinen M, Pääkkönen M, Jokinen R, Kaye S, Heinonen S, Virtanen KA, Andersson DP, Männistö V, Saris WH, Astrup A, Rydén M, Blaak EE, Pajukanta P, Pihlajamäki J, Pietiläinen KH. Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery. J Clin Endocrinol Metab 2021; 106:1312-1324. [PMID: 33560372 PMCID: PMC8063261 DOI: 10.1210/clinem/dgab072] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Indexed: 12/13/2022]
Abstract
CONTEXT Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown. OBJECTIVE To investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies. METHODS The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up. RESULTS Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001). CONCLUSIONS Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.
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Affiliation(s)
- Birgitta W van der Kolk
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Maheswary Muniandy
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Arthur Ko
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Zong Miao
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
| | - Armand Valsesia
- Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland
| | - Dominique Langin
- Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paul Sabatier, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
- Department of Biochemistry, Toulouse University Hospitals, France
| | - Maija Vaittinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Mirva Pääkkönen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Finland
| | - Riikka Jokinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Sanna Kaye
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Sini Heinonen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
| | - Kirsi A Virtanen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
- Turku PET Center, Turku University Hospital, Turku, Finland
| | - Daniel P Andersson
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Wim H Saris
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, The Netherlands
| | - Arne Astrup
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Mikael Rydén
- Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Ellen E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, MD Maastricht, The Netherlands
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA
- Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland
- Obesity Center, Abdominal center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Paczkowska-Abdulsalam M, Kretowski A. Obesity, metabolic health and omics: Current status and future directions. World J Diabetes 2021; 12:420-436. [PMID: 33889288 PMCID: PMC8040086 DOI: 10.4239/wjd.v12.i4.420] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
The growing obesity epidemic is becoming a major public health concern, and the associated costs represent a considerable burden on societies. Among the most common complications of severe obesity are the development of hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, and various types of cancer. Interestingly, some obese individuals have a favorable metabolic profile and appear to be somehow protected from the detrimental effects of excessive adipose tissue accumulation. These individuals remain normoglycemic, insulin sensitive, and hypotensive with proper blood lipid levels, despite their high body mass index and/or waist circumference. Multiple independent observations have led to the concept of the metabolically healthy obese (MHO) phenotype, yet no consensus has been reached to date regarding a universal definition or the main mechanism behind this phenomenon. Recent technological advances and the use of high-throughput analysis techniques have revolutionized different areas of biomedical research. A multi-omics approach, which is used to investigate changes at different molecular levels in an organism or tissue, may provide valuable insights into the interplay between the molecules or pathways and the roles of different factors involved in the mechanisms underlying metabolic health deterioration. The aim of this review is to present the current status regarding the use of omics technologies to investigate the MHO phenotype, as well as the results of targeted analyses conducted in MHO individuals.
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Affiliation(s)
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok 15-276, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok 15-276, Poland
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26
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Dashti M, Alsaleh H, Eaaswarkhanth M, John SE, Nizam R, Melhem M, Hebbar P, Sharma P, Al-Mulla F, Thanaraj TA. Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait. Front Genet 2021; 12:626260. [PMID: 33659027 PMCID: PMC7920096 DOI: 10.3389/fgene.2021.626260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/13/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND/OBJECTIVES Whole-exome sequencing is a valuable tool to determine genetic variations that are associated with rare and common health conditions. A limited number of studies demonstrated that mitochondrial DNA can be captured using whole-exome sequencing. Previous studies have suggested that mitochondrial DNA variants and haplogroup lineages are associated with obesity. Therefore, we investigated the role of mitochondrial variants and haplogroups contributing to the risk of obesity in Arabs in Kuwait using exome sequencing data. SUBJECTS/METHODS Indirect mitochondrial genomes were extracted from exome sequencing data from 288 unrelated native Arab individuals from Kuwait. The cohort was divided into obese [body mass index (BMI) ≥ 30 kg/m2] and non-obese (BMI < 30 kg/m2) groups. Mitochondrial variants were identified, and haplogroups were classified and compared with other sequencing technologies. Statistical analysis was performed to determine associations and identify mitochondrial variants and haplogroups affecting obesity. RESULTS Haplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046). Significant differences in mitochondrial variants between the obese and non-obese groups were mainly haplogroup-defining mutations and were involved in processes in energy generation. The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing. CONCLUSIONS This is the first to utilize whole-exome data to extract entire mitochondrial haplogroups to study its association with obesity in an Arab population.
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Affiliation(s)
- Mohammed Dashti
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Hussain Alsaleh
- Kuwait Identification DNA Laboratory, General Department of Criminal Evidence, Ministry of Interior, Kuwait City, Kuwait
| | | | - Sumi Elsa John
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Rasheeba Nizam
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Motasem Melhem
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Prashantha Hebbar
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Prem Sharma
- Department Special Services Facilities, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
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27
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Pant R, Firmal P, Shah VK, Alam A, Chattopadhyay S. Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome. Front Cell Dev Biol 2021; 8:619888. [PMID: 33511131 PMCID: PMC7835429 DOI: 10.3389/fcell.2020.619888] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals' genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.
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Affiliation(s)
- Richa Pant
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Priyanka Firmal
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Vibhuti Kumar Shah
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Aftab Alam
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Samit Chattopadhyay
- National Centre for Cell Science, SP Pune University Campus, Pune, India.,Department of Biological Sciences, BITS Pilani, Goa, India
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Bardugo A, Bendor CD, Zucker I, Lutski M, Cukierman-Yaffe T, Derazne E, Mosenzon O, Tzur D, Beer Z, Pinhas-Hamiel O, Ben-Ami M, Fishman B, Ben-Ami Shor D, Raz I, Afek A, Gerstein HC, Häring HU, Tirosh A, Levi Z, Twig G. Adolescent Nonalcoholic Fatty Liver Disease and Type 2 Diabetes in Young Adulthood. J Clin Endocrinol Metab 2021; 106:e34-e44. [PMID: 33075820 DOI: 10.1210/clinem/dgaa753] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Indexed: 02/08/2023]
Abstract
CONTEXT The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. OBJECTIVE To assess type 2 diabetes risk among adolescents with NAFLD. DESIGN AND SETTING A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997-2011 and were followed until December 31, 2016. PARTICIPANTS A total of 1 025 796 normoglycemic adolescents were included. INTERVENTIONS Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. MAIN OUTCOME MEASURES Type 2 diabetes incidence. RESULTS During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47-4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). CONCLUSIONS Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.
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Affiliation(s)
- Aya Bardugo
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Cole D Bendor
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Inbar Zucker
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Israel Center for Disease Control, Ministry of Health, Ramat Gan, Israel
| | - Miri Lutski
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- The Israel Center for Disease Control, Ministry of Health, Ramat Gan, Israel
| | - Tali Cukierman-Yaffe
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Estela Derazne
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ofri Mosenzon
- The Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dorit Tzur
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Zivan Beer
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
| | - Orit Pinhas-Hamiel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Michal Ben-Ami
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Boris Fishman
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Internal Medicine D and Hypertension Unit, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Dana Ben-Ami Shor
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Gastroenterology, Tel-Aviv Medical Center, Tel Aviv, Israel
| | - Itamar Raz
- The Diabetes Unit, Department of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Arnon Afek
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Central Management, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | | | - Hans-Ulrich Häring
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Tübingen, Germany
| | - Amir Tirosh
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
| | - Zohar Levi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel
| | - Gilad Twig
- Department of Military Medicine, Hebrew University, Jerusalem and the Israel Defense Forces Medical Corps, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
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F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes. Int J Obes (Lond) 2020; 45:577-587. [PMID: 33221826 DOI: 10.1038/s41366-020-00722-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/10/2020] [Accepted: 11/05/2020] [Indexed: 11/08/2022]
Abstract
OBJECTIVE F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.
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Kaartinen MT, Arora M, Heinonen S, Rissanen A, Kaprio J, Pietiläinen KH. Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response. Int J Mol Sci 2020; 21:E8289. [PMID: 33167412 PMCID: PMC7663854 DOI: 10.3390/ijms21218289] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/11/2022] Open
Abstract
Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy-lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy-Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.
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Affiliation(s)
- Mari T. Kaartinen
- Faculty of Medicine (Experimental Medicine), McGill University, Montreal, QC H3A 0J7, Canada;
- Faculty of Dentistry (Biomedical Sciences), McGill University, Montreal, QC H3A 0J7, Canada
| | - Mansi Arora
- Faculty of Medicine (Experimental Medicine), McGill University, Montreal, QC H3A 0J7, Canada;
| | - Sini Heinonen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.H.); (A.R.); (K.H.P.)
| | - Aila Rissanen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.H.); (A.R.); (K.H.P.)
| | - Jaakko Kaprio
- Department of Public Health, University of Helsinki, 00100 Helsinki, Finland;
| | - Kirsi H. Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; (S.H.); (A.R.); (K.H.P.)
- Abdominal Center, Obesity Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, 00014 Helsinki, Finland
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31
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Kibble M, Khan SA, Ammad-ud-din M, Bollepalli S, Palviainen T, Kaprio J, Pietiläinen KH, Ollikainen M. An integrative machine learning approach to discovering multi-level molecular mechanisms of obesity using data from monozygotic twin pairs. ROYAL SOCIETY OPEN SCIENCE 2020; 7:200872. [PMID: 33204460 PMCID: PMC7657920 DOI: 10.1098/rsos.200872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/29/2020] [Indexed: 05/19/2023]
Abstract
We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m-2). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
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Affiliation(s)
- Milla Kibble
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
- Author for correspondence: Milla Kibble e-mail:
| | - Suleiman A. Khan
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Muhammad Ammad-ud-din
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Sailalitha Bollepalli
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Teemu Palviainen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Jaakko Kaprio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Kirsi H. Pietiläinen
- Obesity Research Unit, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Miina Ollikainen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Orsso CE, Colin-Ramirez E, Field CJ, Madsen KL, Prado CM, Haqq AM. Adipose Tissue Development and Expansion from the Womb to Adolescence: An Overview. Nutrients 2020; 12:E2735. [PMID: 32911676 PMCID: PMC7551046 DOI: 10.3390/nu12092735] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 08/29/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
Prevalence rates of pediatric obesity continue to rise worldwide. Adipose tissue (AT) development and expansion initiate in the fetus and extend throughout the lifespan. This paper presents an overview of the AT developmental trajectories from the intrauterine period to adolescence; factors determining adiposity expansion are also discussed. The greatest fetal increases in AT were observed in the third pregnancy trimester, with growing evidence suggesting that maternal health and nutrition, toxin exposure, and genetic defects impact AT development. From birth up to six months, healthy term newborns experience steep increases in AT; but a subsequent reduction in AT is observed during infancy. Important determinants of AT in infancy identified in this review included feeding practices and factors shaping the gut microbiome. Low AT accrual rates are maintained up to puberty onset, at which time, the pattern of adiposity expansion becomes sex dependent. As girls experience rapid increases and boys experience decreases in AT, sexual dimorphism in hormone secretion can be considered the main contributor for changes. Eating patterns/behaviors and interactions between dietary components, gut microbiome, and immune cells also influence AT expansion. Despite the plasticity of this tissue, substantial evidence supports that adiposity at birth and infancy highly influences its levels across subsequent life stages. Thus, a unique window of opportunity for the prevention and/or slowing down of the predisposition toward obesity, exists from pregnancy through childhood.
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Affiliation(s)
- Camila E. Orsso
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada; (C.E.O.); (C.J.F.); (C.M.P.)
| | | | - Catherine J. Field
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada; (C.E.O.); (C.J.F.); (C.M.P.)
| | - Karen L. Madsen
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2C2, Canada;
| | - Carla M. Prado
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2E1, Canada; (C.E.O.); (C.J.F.); (C.M.P.)
| | - Andrea M. Haqq
- Department of Pediatrics and Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R7, Canada
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Zhou Z, Moore TM, Drew BG, Ribas V, Wanagat J, Civelek M, Segawa M, Wolf DM, Norheim F, Seldin MM, Strumwasser AR, Whitney KA, Lester E, Reddish BR, Vergnes L, Reue K, Rajbhandari P, Tontonoz P, Lee J, Mahata SK, Hewitt SC, Shirihai O, Gastonbury C, Small KS, Laakso M, Jensen J, Lee S, Drevon CA, Korach KS, Lusis AJ, Hevener AL. Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling. Sci Transl Med 2020; 12:eaax8096. [PMID: 32759275 PMCID: PMC8212422 DOI: 10.1126/scitranslmed.aax8096] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 11/04/2019] [Accepted: 07/16/2020] [Indexed: 12/14/2022]
Abstract
Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue ESR1/Esr1 expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, Esr1 was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1 We identified Polg1 as an ERα target gene by showing that ERα binds the Polg1 promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.
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Affiliation(s)
- Zhenqi Zhou
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Timothy M Moore
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Brian G Drew
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Vicent Ribas
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Jonathan Wanagat
- Division of Geriatrics, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Mete Civelek
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Mayuko Segawa
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Dane M Wolf
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Frode Norheim
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Marcus M Seldin
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Alexander R Strumwasser
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Kate A Whitney
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Ellen Lester
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Britany R Reddish
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Laurent Vergnes
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Karen Reue
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Prashant Rajbhandari
- Department of Pathology and Laboratory Medicine and the Howard Hughes Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine and the Howard Hughes Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Jason Lee
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Sushil K Mahata
- VA San Diego Healthcare System, San Diego, CA 92161, USA
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Sylvia C Hewitt
- Receptor Biology Section, NIEHS, NIH, Research Triangle Park, NC 27709, USA
| | - Orian Shirihai
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Craig Gastonbury
- Department of Twin Research and Genetic Epidemiology, King's College London, London SE17EH, UK
| | - Kerrin S Small
- Department of Twin Research and Genetic Epidemiology, King's College London, London SE17EH, UK
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland
| | - Jorgen Jensen
- Department of Physical Performance, Norwegian School of Sport Science, Oslo 0806, Norway
| | - Sindre Lee
- University Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo 0316, Norway
| | - Christian A Drevon
- University Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo 0316, Norway
| | - Kenneth S Korach
- Receptor Biology Section, NIEHS, NIH, Research Triangle Park, NC 27709, USA
| | - Aldons J Lusis
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Andrea L Hevener
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, University of California, Los Angeles, CA 90095, USA.
- Iris Cantor-UCLA Women's Health Research Center, Los Angeles, CA 90095, USA
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Nijhawans P, Behl T, Bhardwaj S. Angiogenesis in obesity. Biomed Pharmacother 2020; 126:110103. [PMID: 32200253 DOI: 10.1016/j.biopha.2020.110103] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Angiogenesis is considered as a major progenitor in the progression of obesity. The current manuscript enumerates the extrinsic role of angiogenesis in obesity. RESULT High caloric diet and lack of physical exercise are the most common causes of obesity and related metabolic conditions. A grossly elevated levels of fat in adipose tissue escalate certain complications which further worsen the state of obesity. Enlargement of white adipose tissue (WAT), deposition of fat mass, proliferation of endothelial cells, production of inflammatory cytokines induces the formation of denovo capillaries from parent microvasculature. Also, several intracellular signaling pathways precipitate obesity. Though, angiostatic molecules (endostatin, angiostatin and TNP-470) have been designed to combat obesity and associated complications. CONCLUSION Adipose tissue trigger growth of blood capillaries, and in turn adipose tissue endothelial cells promote pre-adipocyte proliferation. Modulation of angiogenesis and treatment with angiostatic substances may have the potential to impair the progression of obesity.
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Affiliation(s)
- Priya Nijhawans
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
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Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med 2020; 7:22. [PMID: 32158768 PMCID: PMC7052117 DOI: 10.3389/fcvm.2020.00022] [Citation(s) in RCA: 738] [Impact Index Per Article: 147.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.
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Affiliation(s)
- Alan Chait
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
| | - Laura J den Hartigh
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, United States
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Heinonen S, Jokinen R, Rissanen A, Pietiläinen KH. White adipose tissue mitochondrial metabolism in health and in obesity. Obes Rev 2020; 21:e12958. [PMID: 31777187 DOI: 10.1111/obr.12958] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022]
Abstract
White adipose tissue is one of the largest organs of the body. It plays a key role in whole-body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well-being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity-associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole-body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long-term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue.
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Affiliation(s)
- Sini Heinonen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Riikka Jokinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Aila Rissanen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
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FinnTwin16: A Longitudinal Study from Age 16 of a Population-Based Finnish Twin Cohort. Twin Res Hum Genet 2019; 22:530-539. [PMID: 31796134 DOI: 10.1017/thg.2019.106] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The purpose of this review is to provide a detailed and updated description of the FinnTwin16 (FT16) study and its future directions. The Finnish Twin Cohort comprises three different cohorts: the Older Twin Cohort established in the 1970s and the FinnTwin12 and FT16 initiated in the 1990s. FT16 was initiated in 1991 to identify the genetic and environmental precursors of alcoholism, but later the scope of the project expanded to studying the determinants of various health-related behaviors and diseases in different stages of life. The main areas addressed are alcohol use and its consequences, smoking, physical activity, overall physical health, eating behaviors and eating disorders, weight development, obesity, life satisfaction and personality. To date, five waves of data collection have been completed and the sixth is now planned. Data from the FT16 cohort have contributed to several hundred studies and many substudies, with more detailed phenotyping and collection of omics data completed or underway. FT16 has also contributed to many national and international collaborations.
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Li WC, Chen JY, Liu YP, Lee YY, Yeh WC, Yu W, Tsao YC. Association between metabolic body composition status and risk for impaired renal function: A cross-sectional study. PLoS One 2019; 14:e0223664. [PMID: 31770376 PMCID: PMC6879116 DOI: 10.1371/journal.pone.0223664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/25/2019] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The risk for obesity-related disorders is proportional to the visceral region and had been observed to be highly related with impaired renal function. In the current study, we aimed to evaluate renal function impairment, according to sex, age, and different status of metabolic body composition. METHODS We retrospectively collected from the medical records the basic information and metabolic titers of Chinese adults (13,373 men and 10,175 women) who underwent health checkup from 2013 to 2016. The population was divided into four groups, according to metabolic body composition, including metabolic healthy norms-weight (MHNW), metabolic healthy obesity (MHO), metabolic unhealthy norms-weight (MUNW), and metabolic unhealthy obesity (MUO). The categorical data were compared among the groups and logistic regression analyses were conducted to investigate the association between metabolic body composition status and risk for renal function impairment. RESULTS Across all ages in both sexes, the odds ratios (OR) for renal function impairment were higher in the MHO, MUNW, and MUO groups than in the MHNW group, except for women <45 years old in the MUNW group. However, after adjustment, the trend was no longer significant in all groups under 45 years old. For individuals >45 years old, the relatively high risk for renal function impairment remained significantly associated with the MUNW group (OR 2.95, 95% CI 2.02-4.30 in men and OR 1.95, 95% CI 1.35-2.82 in women) and MUO group (OR 2.33, 95% CI 1.82-3.00 in men and OR 2.67, 95% CI 2.04-3.48 in women). CONCLUSION Impaired renal function was independently associated with the status of metabolic obesity. However, the trend was only observed in individuals >45 years old, with significant sex difference.
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Affiliation(s)
- Wen-Cheng Li
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Health Management, Xiamen Chang-Gung Hospital, Xiamen, China
| | - Jau-Yuan Chen
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Ping Liu
- Department of Endocrinology and Metabolism, Xiamen Chang-Gung Hospital, Xiamen, China
| | - Yi-Yen Lee
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Chung Yeh
- Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei Yu
- Department of Health Management, Xiamen Chang-Gung Hospital, Xiamen, China
| | - Yu-Chung Tsao
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Health Management, Xiamen Chang-Gung Hospital, Xiamen, China
- Department of Occupational Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- * E-mail:
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Bogl LH, Kaprio J, Pietiläinen KH. Dietary n-6 to n-3 fatty acid ratio is related to liver fat content independent of genetic effects: Evidence from the monozygotic co-twin control design. Clin Nutr 2019; 39:2311-2314. [PMID: 31668723 DOI: 10.1016/j.clnu.2019.10.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/04/2019] [Accepted: 10/07/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIM Lifestyle changes focusing on diet and exercise remain the cornerstone of the treatment of non-alcoholic fatty liver disease (NAFLD). The present co-twin control study of monozygotic (MZ) twin pairs was designed to identify nutritional factors potentially involved in the pathogenesis of NAFLD. METHODS Cross-sectional study of 50 MZ twin pairs (age range: 23-36 years), of which ten pairs were discordant for liver fat (liver fat percentage of one twin ≤5% and his/her co-twin >5% and a difference between co-twins of >5%) as determined by magnetic resonance spectroscopy. Nutrient intake was calculated from 3-day food records. RESULTS Among the ten liver fat-discordant twin pairs, the n-6: n-3 ratio was significantly higher in the twins with higher liver as compared to their co-twins with lower liver fat (6.6:1 vs. 3.2:1, p-value = 0.005). In multiple regression analysis of within-pair differences including all 50 twin pairs, a higher n-6: n-3 ratio was significantly associated with a higher liver fat percentage within MZ twin pairs after adjustment for body mass index, energy intake and other covariates (standardized beta = 0.43, p-value = 0.001). CONCLUSIONS Our findings suggest that the n-6: n-3 ratio is a promising dietary agent for the prevention and treatment of NAFLD. Clinical trials are required to better understand causal relationships and required doses.
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Affiliation(s)
- Leonie H Bogl
- Department of Epidemiology, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria; Institute for Molecular Medicine FIMM, University of Helsinki, 00014, Helsinki, Finland.
| | - Jaakko Kaprio
- Institute for Molecular Medicine FIMM, University of Helsinki, 00014, Helsinki, Finland; Department of Public Health, University of Helsinki, 00014, Helsinki, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland; Abdominal Center, Endocrinology, Helsinki University Central Hospital and University of Helsinki, 00014, Helsinki, Finland
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Tran HQ, Mills RH, Peters NV, Holder MK, de Vries GJ, Knight R, Chassaing B, Gonzalez DJ, Gewirtz AT. Associations of the Fecal Microbial Proteome Composition and Proneness to Diet-induced Obesity. Mol Cell Proteomics 2019; 18:1864-1879. [PMID: 31262998 PMCID: PMC6731084 DOI: 10.1074/mcp.ra119.001623] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Indexed: 12/16/2022] Open
Abstract
Consumption of refined high-fat, low-fiber diets promotes development of obesity and its associated consequences. Although genetics play an important role in dictating susceptibility to such obesogenic diets, mice with nearly uniform genetics exhibit marked heterogeneity in their extent of obesity in response to such diets. This suggests non-genetic determinants play a role in diet-induced obesity. Hence, we sought to identify parameters that predict, and/or correlate with, development of obesity in response to an obesogenic diet. We assayed behavior, metabolic parameters, inflammatory markers/cytokines, microbiota composition, and the fecal metaproteome, in a cohort of mice (n = 50) prior to, and the 8 weeks following, administration of an obesogenic high-fat low-fiber diet. Neither behavioral testing nor quantitation of inflammatory markers broadly predicted severity of diet-induced obesity. Although, the small subset of mice that exhibited basal elevations in serum IL-6 (n = 5) were among the more obese mice in the cohort. While fecal microbiota composition changed markedly in response to the obesogenic diet, it lacked the ability to predict which mice were relative prone or resistant to obesity. In contrast, fecal metaproteome analysis revealed functional and taxonomic differences among the proteins associated with proneness to obesity. Targeted interrogation of microbiota composition data successfully validated the taxonomic differences seen in the metaproteome. Although future work will be needed to determine the breadth of applicability of these associations to other cohorts of animals and humans, this study nonetheless highlights the potential power of gut microbial proteins to predict and perhaps impact development of obesity.
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Affiliation(s)
- Hao Q Tran
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA
| | - Robert H Mills
- §Department of Pharmacology, University of California, San Diego, CA; ¶Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA; ‖Department of Pediatrics, and Department of Computer Science and Engineering, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA
| | - Nicole V Peters
- ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA
| | - Mary K Holder
- ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA; §§School of Psychology, Georgia Institute of Technology, Atlanta, GA 30332
| | | | - Rob Knight
- ‖Department of Pediatrics, and Department of Computer Science and Engineering, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA
| | - Benoit Chassaing
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA; ‡‡Neuroscience Institute, Georgia State University, Atlanta, GA
| | - David J Gonzalez
- §Department of Pharmacology, University of California, San Diego, CA; ¶Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA; **Center for Microbiome Innovation, University of California, San Diego, CA.
| | - Andrew T Gewirtz
- ‡Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA.
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Gepner Y, Shelef I, Komy O, Cohen N, Schwarzfuchs D, Bril N, Rein M, Serfaty D, Kenigsbuch S, Zelicha H, Yaskolka Meir A, Tene L, Bilitzky A, Tsaban G, Chassidim Y, Sarusy B, Ceglarek U, Thiery J, Stumvoll M, Blüher M, Stampfer MJ, Rudich A, Shai I. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J Hepatol 2019; 71:379-388. [PMID: 31075323 DOI: 10.1016/j.jhep.2019.04.013] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 03/26/2019] [Accepted: 04/17/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIM It is unclear if a reduction in hepatic fat content (HFC) is a major mediator of the cardiometabolic benefit of lifestyle intervention, and whether it has prognostic significance beyond the loss of visceral adipose tissue (VAT). In the present sub-study, we hypothesized that HFC loss in response to dietary interventions induces specific beneficial effects independently of VAT changes. METHODS In an 18-month weight-loss trial, 278 participants with abdominal obesity/dyslipidemia were randomized to low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC + 28 g walnuts/day) diets with/without moderate physical activity. HFC and abdominal fat-depots were measured using magnetic resonance imaging at baseline, after 6 (sub-study, n = 158) and 18 months. RESULTS Of 278 participants (mean HFC 10.2% [range: 0.01%-50.4%]), the retention rate was 86.3%. The %HFC substantially decreased after 6 months (-6.6% absolute units [-41% relatively]) and 18 months (-4.0% absolute units [-29% relatively]; p <0.001 vs. baseline). Reductions of HFC were associated with decreases in VAT beyond weight loss. After controlling for VAT loss, decreased %HFC remained independently associated with reductions in serum gamma glutamyltransferase and alanine aminotransferase, circulating chemerin, and glycated hemoglobin (p <0.05). While the reduction in HFC was similar between physical activity groups, MED/LC induced a greater %HFC decrease (p = 0.036) and greater improvements in cardiometabolic risk parameters (p <0.05) than the LF diet, even after controlling for VAT changes. Yet, the greater improvements in cardiometabolic risk parameters induced by MED/LC were all markedly attenuated when controlling for HFC changes. CONCLUSIONS %HFC is substantially reduced by diet-induced moderate weight loss and is more effectively reduced by the MED/LC diet than the LF diet, independently of VAT changes. The beneficial effects of the MED/LC diet on specific cardiometabolic parameters appear to be mediated more by decreases in %HFC than VAT loss. LAY SUMMARY High hepatic fat content is associated with metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease. In the CENTRAL 18-month intervention trial, a Mediterranean/low-carbohydrate diet induced a greater decrease in hepatic fat content than a low-fat diet, conferring beneficial health effects that were beyond the favorable effects of visceral fat loss. ClinicalTrials.gov Identifier: NCT01530724.
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Affiliation(s)
- Yftach Gepner
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine and Sylvan Adams Sports Institute, Tel Aviv University, Israel
| | - Ilan Shelef
- Soroka University Medical Center, Beer-Sheva, Israel
| | - Oded Komy
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Noa Cohen
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Dan Schwarzfuchs
- Soroka University Medical Center, Beer-Sheva, Israel; Nuclear Research Center-Negev, Dimona, Israel
| | - Nitzan Bril
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Michal Rein
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Dana Serfaty
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Shira Kenigsbuch
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hila Zelicha
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Anat Yaskolka Meir
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Lilac Tene
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Avital Bilitzky
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Gal Tsaban
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | | | | | - Uta Ceglarek
- Department of Medicine, University of Leipzig, Germany
| | | | | | | | - Meir J Stampfer
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard School of Public Health, Boston, MA, USA
| | - Assaf Rudich
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Iris Shai
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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Sun W, von Meyenn F, Peleg‐Raibstein D, Wolfrum C. Environmental and Nutritional Effects Regulating Adipose Tissue Function and Metabolism Across Generations. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1900275. [PMID: 31179229 PMCID: PMC6548959 DOI: 10.1002/advs.201900275] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/21/2019] [Indexed: 05/12/2023]
Abstract
The unabated rise in obesity prevalence during the last 40 years has spurred substantial interest in understanding the reasons for this epidemic. Studies in mice and humans have demonstrated that obesity is a highly heritable disease; however genetic variations within specific populations have so far not been able to explain this phenomenon to its full extent. Recent work has demonstrated that environmental cues can be sensed by an organism to elicit lasting changes, which in turn can affect systemic energy metabolism by different epigenetic mechanisms such as changes in small noncoding RNA expression, DNA methylation patterns, as well as histone modifications. These changes can directly modulate cellular function in response to environmental cues, however research during the last decade has demonstrated that some of these modifications might be transmitted to subsequent generations, thus modulating energy metabolism of the progeny in an inter- as well as transgenerational manner. In this context, adipose tissue has become a focus of research due to its plasticity, which allows the formation of energy storing (white) as well as energy wasting (brown/brite/beige) cells within the same depot. In this Review, the effects of environmental induced obesity with a particular focus on adipose tissue are discussed.
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Affiliation(s)
- Wenfei Sun
- Department of Health Science and TechnologiesETH ZürichSchorenstrasse 16SchwerzenbachCH‐8603Switzerland
| | - Ferdinand von Meyenn
- Department of Health Science and TechnologiesETH ZürichSchorenstrasse 16SchwerzenbachCH‐8603Switzerland
| | - Daria Peleg‐Raibstein
- Department of Health Science and TechnologiesETH ZürichSchorenstrasse 16SchwerzenbachCH‐8603Switzerland
| | - Christian Wolfrum
- Department of Health Science and TechnologiesETH ZürichSchorenstrasse 16SchwerzenbachCH‐8603Switzerland
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Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Beguinot F, Miele C. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int J Mol Sci 2019; 20:ijms20092358. [PMID: 31085992 PMCID: PMC6539070 DOI: 10.3390/ijms20092358] [Citation(s) in RCA: 978] [Impact Index Per Article: 163.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023] Open
Abstract
Obesity is a critical risk factor for the development of type 2 diabetes (T2D), and its prevalence is rising worldwide. White adipose tissue (WAT) has a crucial role in regulating systemic energy homeostasis. Adipose tissue expands by a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). The recruitment and differentiation of adipose precursor cells in the subcutaneous adipose tissue (SAT), rather than merely inflating the cells, would be protective from the obesity-associated metabolic complications. In metabolically unhealthy obesity, the storage capacity of SAT, the largest WAT depot, is limited, and further caloric overload leads to the fat accumulation in ectopic tissues (e.g., liver, skeletal muscle, and heart) and in the visceral adipose depots, an event commonly defined as “lipotoxicity.” Excessive ectopic lipid accumulation leads to local inflammation and insulin resistance (IR). Indeed, overnutrition triggers uncontrolled inflammatory responses in WAT, leading to chronic low-grade inflammation, therefore fostering the progression of IR. This review summarizes the current knowledge on WAT dysfunction in obesity and its associated metabolic abnormalities, such as IR. A better understanding of the mechanisms regulating adipose tissue expansion in obesity is required for the development of future therapeutic approaches in obesity-associated metabolic complications.
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Affiliation(s)
- Michele Longo
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Federica Zatterale
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Jamal Naderi
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Luca Parrillo
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Pietro Formisano
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Gregory Alexander Raciti
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Francesco Beguinot
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
| | - Claudia Miele
- Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
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Bermingham KM, Brennan L, Segurado R, Barron RE, Gibney ER, Ryan MF, Gibney MJ, O’Sullivan AM. Exploring Covariation between Traditional Markers of Metabolic Health and the Plasma Metabolomic Profile: A Classic Twin Design. J Proteome Res 2019; 18:2613-2623. [DOI: 10.1021/acs.jproteome.9b00126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Kate M. Bermingham
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Lorraine Brennan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Ricardo Segurado
- School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Rebecca E. Barron
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Eileen R. Gibney
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Miriam F. Ryan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Michael J. Gibney
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - Aifric M. O’Sullivan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
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Sahebekhtiari N, Saraswat M, Joenväärä S, Jokinen R, Lovric A, Kaye S, Mardinoglu A, Rissanen A, Kaprio J, Renkonen R, Pietiläinen KH. Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs. Proteomics Clin Appl 2019; 13:e1800173. [PMID: 30688043 DOI: 10.1002/prca.201800173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/27/2018] [Indexed: 01/24/2023]
Abstract
PURPOSE The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. EXPERIMENTAL DESIGN The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m-2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy. RESULTS Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. CONCLUSIONS AND CLINICAL RELEVANCE The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.
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Affiliation(s)
- Navid Sahebekhtiari
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland
| | - Mayank Saraswat
- Transplantation Laboratory, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Sakari Joenväärä
- Transplantation Laboratory, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Riikka Jokinen
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland
| | - Alen Lovric
- Science for Life Laboratory, KTH-Royal Institute of Technology, 17121, Stockholm, Sweden
| | - Sanna Kaye
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, 17121, Stockholm, Sweden.,Department of Biology and Biological Engineering, Chalmers University of Technology, 41296, Gothenburg, Sweden.,Centre for Host-Microbiome Interactions, Dental Institute, King's College London, SE19RT, London, UK
| | - Aila Rissanen
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland
| | - Jaakko Kaprio
- Department of Public Health, Finnish Twin Cohort Study, University of Helsinki, 00014, Helsinki, Finland.,Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014, Helsinki, Finland
| | - Risto Renkonen
- Transplantation Laboratory, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, 00014, Helsinki, Finland.,Abdominal Center, Endocrinology, Helsinki University Central Hospital and University of Helsinki, 00014, Helsinki, Finland
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Vihma V, Heinonen S, Naukkarinen J, Kaprio J, Rissanen A, Turpeinen U, Hämäläinen E, Hakkarainen A, Lundbom J, Lundbom N, Mikkola TS, Tikkanen MJ, Pietiläinen KH. Increased body fat mass and androgen metabolism - A twin study in healthy young women. Steroids 2018; 140:24-31. [PMID: 30149073 DOI: 10.1016/j.steroids.2018.08.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 08/15/2018] [Accepted: 08/21/2018] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Obesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. DESIGN Age and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23-36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). METHODS We determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. RESULTS The heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P < 0.05 for all) compared to their leaner co-twins with no differences in serum testosterone or androstenedione levels. Serum DHEA correlated inversely with %body fat (r = -0.905, P = 0.002), and DHT positively with SHBG (r = 0.842, P = 0.002). In adipose tissue or adipocytes, expressions of STS (steroid sulfatase) and androgen-related genes were significantly higher in the heavier compared to the leaner co-twin, and within pairs, correlated positively with adiposity but were not related to serum androgen levels. None of the serum androgen or SHBG levels correlated with indices of insulin resistance. CONCLUSIONS Serum DHEA levels were best predicted by %body fat, and serum DHT by SHBG. These or other serum androgen concentrations did not reflect differences in androgen-related genes in adipose tissue. General or intra-abdominal adiposity were not associated with increased androgenicity in young women.
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Affiliation(s)
- Veera Vihma
- University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Biomedicum C315a, Haartmaninkatu 8, 00290 Helsinki, Finland; Folkhälsan Research Center, P.O. Box 63, 00014 University of Helsinki, Finland.
| | - Sini Heinonen
- University of Helsinki, Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, P.O. Box 63, 00014 University of Helsinki, Finland
| | - Jussi Naukkarinen
- University of Helsinki, Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, P.O. Box 63, 00014 University of Helsinki, Finland
| | - Jaakko Kaprio
- University of Helsinki, FIMM, Institute for Molecular Medicine Finland, and Department of Public Health, P.O. Box 20, 00014 University of Helsinki, Finland
| | - Aila Rissanen
- University of Helsinki, Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, P.O. Box 63, 00014 University of Helsinki, Finland
| | - Ursula Turpeinen
- Helsinki University Hospital, HUSLAB, P.O. Box 720, 00029 HUS, Helsinki, Finland
| | - Esa Hämäläinen
- Helsinki University Hospital, HUSLAB, P.O. Box 720, 00029 HUS, Helsinki, Finland
| | - Antti Hakkarainen
- University of Helsinki and HUS Medical Imaging Center, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Jesper Lundbom
- University of Helsinki and HUS Medical Imaging Center, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Nina Lundbom
- University of Helsinki and HUS Medical Imaging Center, Helsinki University Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Tomi S Mikkola
- Folkhälsan Research Center, P.O. Box 63, 00014 University of Helsinki, Finland; Helsinki University Hospital, Obstetrics and Gynecology, P.O. Box 140, 00029 HUS, Helsinki, Finland
| | - Matti J Tikkanen
- University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Biomedicum C315a, Haartmaninkatu 8, 00290 Helsinki, Finland; Folkhälsan Research Center, P.O. Box 63, 00014 University of Helsinki, Finland
| | - Kirsi H Pietiläinen
- University of Helsinki, Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, P.O. Box 63, 00014 University of Helsinki, Finland; Helsinki University Hospital, Endocrinology, Abdominal Center, P.O. Box 340, 00029 HUS, Helsinki, Finland
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Abstract
Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal-weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals, the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the aetiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favourable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery and subsequently through functional follow-up of identified genes.
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Affiliation(s)
- R J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Copenhagen, Denmark
| | - T O Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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48
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Feldman A, Eder SK, Felder TK, Paulweber B, Zandanell S, Stechemesser L, Schranz M, Strebinger G, Huber-Schönauer U, Niederseer D, Patsch W, Weghuber D, Tevini J, Datz C, Aigner E. Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach. DIABETES & METABOLISM 2018; 45:132-139. [PMID: 30266576 DOI: 10.1016/j.diabet.2018.09.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 09/04/2018] [Accepted: 09/10/2018] [Indexed: 01/14/2023]
Abstract
INTRODUCTION As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.
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Affiliation(s)
- A Feldman
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - S K Eder
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - T K Felder
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Laboratory Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - B Paulweber
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - S Zandanell
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - L Stechemesser
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - M Schranz
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria
| | - G Strebinger
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - U Huber-Schönauer
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - D Niederseer
- Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria; Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - W Patsch
- Department of Pharmacology and Toxicology, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - D Weghuber
- Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - J Tevini
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Laboratory Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - C Datz
- Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Internal Medicine, Hospital Oberndorf, Oberndorf, Austria
| | - E Aigner
- First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
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49
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Allison KC, Goel N. Timing of eating in adults across the weight spectrum: Metabolic factors and potential circadian mechanisms. Physiol Behav 2018; 192:158-166. [PMID: 29486170 PMCID: PMC6019166 DOI: 10.1016/j.physbeh.2018.02.047] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 02/23/2018] [Accepted: 02/23/2018] [Indexed: 12/21/2022]
Abstract
Timing of eating is recognized as a significant contributor to body weight regulation. Disruption of sleep-wake cycles from a predominantly diurnal (daytime) to a delayed (evening) lifestyle leads to altered circadian rhythms and metabolic dysfunction. This article reviews current evidence for timed and delayed eating in individuals of normal weight and those with overweight or obesity: although some findings indicate a benefit of eating earlier in the daytime on weight and/or metabolic outcomes, results have not been uniformly consistent, and more rigorous and longer-duration studies are needed. We also review potential circadian mechanisms underlying the metabolic- and weight-related changes resulting from timed and delayed eating. Further identification of such mechanisms using deep phenotyping is required to determine targets for medical interventions for obesity and for prevention of metabolic syndrome and diabetes, and to inform clinical guidelines regarding eating schedules for management of weight and metabolic disease.
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Affiliation(s)
- Kelly C Allison
- Center for Weight and Eating Disorders, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| | - Namni Goel
- Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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50
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Elshorbagy AK, Samocha-Bonet D, Jernerén F, Turner C, Refsum H, Heilbronn LK. Food Overconsumption in Healthy Adults Triggers Early and Sustained Increases in Serum Branched-Chain Amino Acids and Changes in Cysteine Linked to Fat Gain. J Nutr 2018; 148:1073-1080. [PMID: 29901727 DOI: 10.1093/jn/nxy062] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 03/06/2018] [Indexed: 01/03/2023] Open
Abstract
Background Plasma concentrations of branched-chain amino acids (BCAAs) and the sulfur-containing amino acid cysteine are associated with obesity and insulin resistance. BCAAs predict future diabetes. Objective We investigated amino acid changes during food overconsumption. Methods Forty healthy men and women with a body mass index (mean ± SEM) of 25.6 ± 0.6 were overfed by 1250 kcal/d for 28 d, increasing consumption of all macronutrients. Insulin sensitivity and body composition were assessed at baseline (day 0) and day 28. Fasting serum amino acids were measured at days 0, 3, and 28. Linear mixed-effects models evaluated the effect of time in the total group and separately in those with low and high body fat gain (below compared with at or above median fat gain, 1.95 kg). At days 0 and 28, insulin-induced suppression of serum amino acids during a hyperinsulinemic-euglycemic clamp test and, in a subset (n = 20), adipose tissue mRNA expression of selected amino acid metabolizing enzymes were assessed. Results Weight increased by 2.8 kg. High fat gainers gained 2.6 kg fat mass compared with 1.1 kg in low fat gainers. Valine and isoleucine increased at day 3 (+17% and +22%, respectively; P ≤ 0.002) and remained elevated at day 28, despite a decline in valine (P = 0.019) from day 3 values. Methionine, cystathionine, and taurine were unaffected. Serum total cysteine (tCys) transiently increased at day 3 (+11%; P = 0.022) only in high fat gainers (P-interaction = 0.043), in whom the cysteine catabolic enzyme cysteine dioxygenase (CDO1) was induced (+26%; P = 0.025) in adipose tissue (P-interaction = 0.045). Overconsumption did not alter adipose tissue mRNA expression of the BCAA-metabolizing enzymes branched-chain keto acid dehydrogenase E1α polypeptide (BCKDHA) or branched-chain amino transferase 1 (BCAT1). In the total population at day 0, insulin infusion decreased all serum amino acids (-11% to -47%; P < 0.01), except for homocysteine and tCys, which were unchanged, and glutathione, which was increased by 54%. At day 28, insulin increased tCys (+8%), and the insulin-induced suppression of taurine and phenylalanine observed at day 0, but not that of BCAAs, was significantly impaired. Conclusions These findings highlight the role of nutrient oversupply in increasing fasting BCAA concentrations in healthy adults. The link between cysteine availability, CDO1 expression, and fat gain deserves investigation. This trial was registered at www.clinicaltrials.gov as NCT00562393.
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Affiliation(s)
- Amany K Elshorbagy
- Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Dorit Samocha-Bonet
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.,Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia
| | - Fredrik Jernerén
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom.,Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Cheryl Turner
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Helga Refsum
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom.,Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway
| | - Leonie K Heilbronn
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia.,Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
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