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Alradi M, Askari H, Shaw M, Bhavsar JD, Kingham BF, Polson SW, Fancher IS. A long-term high-fat diet induces differential gene expression changes in spatially distinct adipose tissue of male mice. Physiol Genomics 2024; 56:819-832. [PMID: 39348460 PMCID: PMC11573270 DOI: 10.1152/physiolgenomics.00080.2024] [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: 06/16/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024] Open
Abstract
The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, male mice (n = 4) were fed a high-fat diet to induce obesity or a normal laboratory diet (lean controls) for 12-14 mo. Mesenteric VAT and inguinal SAT were isolated for bulk RNA sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high-fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited 308 differentially expressed genes (164 upregulated and 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated and 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT versus downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT versus VAT with respect to obesity.NEW & NOTEWORTHY A long-term high-fat diet induced the expression of more than 980 unique genes across subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). The high-fat diet also induced the differential expression of nearly 1,000 AT genes. We identified four genes that were oppositely expressed in SAT versus VAT in response to the high-fat diet and propose that these genes in particular may serve as promising targets aimed at resolving VAT dysfunction in obesity.
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Affiliation(s)
- Malak Alradi
- Department of Biological Sciences, College of Arts and Sciences, University of Delaware, Newark, Delaware, United States
| | - Hassan Askari
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mark Shaw
- Delware Biotechnology Institute, University of Delaware, Newark, Delaware, United States
| | - Jaysheel D Bhavsar
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, United States
| | - Brewster F Kingham
- Delware Biotechnology Institute, University of Delaware, Newark, Delaware, United States
| | - Shawn W Polson
- Delware Biotechnology Institute, University of Delaware, Newark, Delaware, United States
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, United States
- Department of Computer and Information Sciences, College of Engineering, University of Delaware, Newark, Delaware, United States
| | - Ibra S Fancher
- Department of Biological Sciences, College of Arts and Sciences, University of Delaware, Newark, Delaware, United States
- Department of Kinesiology and Applied Physiology, College of Health Sciences, University of Delaware, Newark, Delaware, United States
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Hofwimmer K, de Paula Souza J, Subramanian N, Vujičić M, Rachid L, Méreau H, Zhao C, Dror E, Barreby E, Björkström NK, Wernstedt Asterholm I, Böni-Schnetzler M, Meier DT, Donath MY, Laurencikiene J. IL-1β promotes adipogenesis by directly targeting adipocyte precursors. Nat Commun 2024; 15:7957. [PMID: 39261467 PMCID: PMC11390900 DOI: 10.1038/s41467-024-51938-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 08/21/2024] [Indexed: 09/13/2024] Open
Abstract
Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.
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Affiliation(s)
- Kaisa Hofwimmer
- Lipid Laboratory, Unit of Endocrinology, Department of Medicine Huddinge, Karolinska Institutet, SE-141 52, Huddinge, Sweden
| | - Joyce de Paula Souza
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Narmadha Subramanian
- Lipid Laboratory, Unit of Endocrinology, Department of Medicine Huddinge, Karolinska Institutet, SE-141 52, Huddinge, Sweden
| | - Milica Vujičić
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-405 30, Gothenburg, Sweden
| | - Leila Rachid
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Hélène Méreau
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Cheng Zhao
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Erez Dror
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Emelie Barreby
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 52, Huddinge, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 52, Huddinge, Sweden
| | - Ingrid Wernstedt Asterholm
- Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, SE-405 30, Gothenburg, Sweden
| | - Marianne Böni-Schnetzler
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Daniel T Meier
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland.
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland.
| | - Marc Y Donath
- Department of Biomedicine, University of Basel and University Hospital Basel, 4031, Basel, Switzerland
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, 4031, Basel, Switzerland
| | - Jurga Laurencikiene
- Lipid Laboratory, Unit of Endocrinology, Department of Medicine Huddinge, Karolinska Institutet, SE-141 52, Huddinge, Sweden.
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Steiner BM, Benvie AM, Lee D, Jiang Y, Berry DC. Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner. Nat Commun 2024; 15:6622. [PMID: 39103342 PMCID: PMC11300861 DOI: 10.1038/s41467-024-50985-8] [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: 08/10/2022] [Accepted: 07/26/2024] [Indexed: 08/07/2024] Open
Abstract
Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.
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Affiliation(s)
- Benjamin M Steiner
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Abigail M Benvie
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Derek Lee
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Yuwei Jiang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Daniel C Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.
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Zambrano C, Garitaonaindia MT, Salmerón D, Pérez-Sanz F, Tchio C, Picinato MC, de Medina FS, Luján J, Scheer FAJL, Saxena R, Martínez-Augustin O, Garaulet M. Melatonin decreases human adipose tissue insulin sensitivity. J Pineal Res 2024; 76:e12965. [PMID: 38860494 DOI: 10.1111/jpi.12965] [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: 02/27/2024] [Revised: 05/07/2024] [Accepted: 05/13/2024] [Indexed: 06/12/2024]
Abstract
Melatonin is a pineal hormone that modulates the circadian system and exerts soporific and phase-shifting effects. It is also involved in many other physiological processes, such as those implicated in cardiovascular, endocrine, immune, and metabolic functions. However, the role of melatonin in glucose metabolism remains contradictory, and its action on human adipose tissue (AT) explants has not been demonstrated. We aimed to assess whether melatonin (a pharmacological dose) influences insulin sensitivity in human AT. This will help better understand melatonin administration's effect on glucose metabolism. Abdominal AT (subcutaneous and visceral) biopsies were obtained from 19 participants with severe obesity (age: 42.84 ± 12.48 years; body mass index: 43.14 ± 8.26 kg/m2) who underwent a laparoscopic gastric bypass. AT biopsies were exposed to four different treatments: control (C), insulin alone (I) (10 nM), melatonin alone (M) (5000 pg/mL), and insulin plus melatonin combined (I + M). All four conditions were repeated in both subcutaneous and visceral AT, and all were performed in the morning at 8 a.m. (n = 19) and the evening at 8 p.m. (in a subsample of n = 12). We used western blot analysis to determine insulin signaling (using the pAKT/tAKT ratio). Furthermore, RNAseq analyses were performed to better understand the metabolic pathways involved in the effect of melatonin on insulin signaling. As expected, insulin treatment (I) increased the pAKT/tAKT ratio compared with control (p < .0001). Furthermore, the addition of melatonin (I + M) resulted in a decrease in insulin signaling as compared with insulin alone (I); this effect was significant only during the evening time (not in the morning time). Further, RNAseq analyses in visceral AT during the evening condition (at 8 p.m.) showed that melatonin resulted in a prompt transcriptome response (around 1 h after melatonin addition), particularly by downregulating the insulin signaling pathway. Our results show that melatonin reduces insulin sensitivity in human AT during the evening. These results may partly explain the previous studies showing a decrease in glucose tolerance after oral melatonin administration in the evening or when eating late when endogenous melatonin is present.
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Affiliation(s)
- Carolina Zambrano
- Department of Physiology, Regional Campus of International Excellence, University of Murcia, Murcia, Spain
- Research Biomedical Institute of Murcia (IMIB)-Arrixaca, Murcia, Spain
| | - Mireia Tena Garitaonaindia
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Ibs Granada, Instituto de Nutrición y Tecnología de los Alimentos (INYTA) José Mataix, University of Granada, Granada, Spain
| | - Diego Salmerón
- Research Biomedical Institute of Murcia (IMIB)-Arrixaca, Murcia, Spain
- Health and Social Sciences Department, University of Murcia, Murcia, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | | | - Cynthia Tchio
- Center for Genomic Medicine, Massachusetts General Hospital, Cambridge, Massachusetts, USA
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA
| | | | - Fermín Sánchez de Medina
- Department of Pharmacology, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Ibs Granada, Universidad de Granada, Granada, Spain
| | - Juan Luján
- General Surgery Service, Hospital Quirónsalud Murcia, Murcia, Spain
| | - Frank A J L Scheer
- Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA
- Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Richa Saxena
- Center for Genomic Medicine, Massachusetts General Hospital, Cambridge, Massachusetts, USA
| | - Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Ibs Granada, Instituto de Nutrición y Tecnología de los Alimentos (INYTA) José Mataix, University of Granada, Granada, Spain
| | - Marta Garaulet
- Department of Physiology, Regional Campus of International Excellence, University of Murcia, Murcia, Spain
- Research Biomedical Institute of Murcia (IMIB)-Arrixaca, Murcia, Spain
- Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Byun KA, Kim HM, Oh S, Batsukh S, Lee S, Oh M, Lee J, Lee R, Kim JW, Oh SM, Kim J, Kim G, Park HJ, Hong H, Lee J, An SH, Oh SS, Jung YS, Son KH, Byun K. High-Intensity Focused Ultrasound Increases Facial Adipogenesis in a Swine Model via Modulation of Adipose-Derived Stem Cell Cilia. Int J Mol Sci 2024; 25:7648. [PMID: 39062891 PMCID: PMC11277104 DOI: 10.3390/ijms25147648] [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: 06/22/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Decreased medial cheek fat volume during aging leads to loss of a youthful facial shape. Increasing facial volume by methods such as adipose-derived stem cell (ASC) injection can produce facial rejuvenation. High-intensity focused ultrasound (HIFU) can increase adipogenesis in subcutaneous fat by modulating cilia on ASCs, which is accompanied by increased HSP70 and decreased NF-κB expression. Thus, we evaluated the effect of HIFU on increasing facial adipogenesis in swine (n = 2) via modulation of ASC cilia. Expression of CD166, an ASC marker, differed by subcutaneous adipose tissue location. CD166 expression in the zygomatic arch (ZA) was significantly higher than that in the subcutaneous adipose tissue in the mandible or lateral temporal areas. HIFU was applied only on the right side of the face, which was compared with the left side, where HIFU was not applied, as a control. HIFU produced a significant increase in HSP70 expression, decreased expression of NF-κB and a cilia disassembly factor (AURKA), and increased expression of a cilia increasing factor (ARL13B) and PPARG and CEBPA, which are the main regulators of adipogenesis. All of these changes were most prominent at the ZA. Facial adipose tissue thickness was also increased by HIFU. Adipose tissue volume, evaluated by magnetic resonance imaging, was increased by HIFU, most prominently in the ZA. In conclusion, HIFU increased ASC marker expression, accompanied by increased HSP70 and decreased NF-κB expression. Additionally, changes in cilia disassembly and length and expression of adipogenesis were observed. These results suggest that HIFU could be used to increase facial volume by modulating adipogenesis.
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Affiliation(s)
- Kyung-A Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- LIBON Inc., Incheon 22006, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Hyoung Moon Kim
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Maylin Clinic, Goyang 10391, Republic of Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sosorburam Batsukh
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sangsu Lee
- Mirabel Clinic, Seoul 04596, Republic of Korea
| | - Myungjune Oh
- GangnamON Clinic, Seoul 06129, Republic of Korea
| | | | - Ran Lee
- Ezen Clinic, Cheonan 31090, Republic of Korea
| | - Jae Woo Kim
- Lienjang Clinic, Seoul 04536, Republic of Korea
| | - Seung Min Oh
- GangnamON Clinic, Seoul 06129, Republic of Korea
| | - Jisun Kim
- MH Clinic, Seoul 06010, Republic of Korea
| | - Geebum Kim
- Misogain Dermatology Clinic, Gimpo 10108, Republic of Korea
| | - Hyun Jun Park
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Maylin Clinic the Cheongdam, Seoul 06091, Republic of Korea
| | - Hanbit Hong
- Lux Well Clinic, Cheongju 28424, Republic of Korea
| | - Jehyuk Lee
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Doctorbom Clinic, Seoul 06614, Republic of Korea
| | - Sang-Hyun An
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Sung Suk Oh
- Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Yeon-Seop Jung
- Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu 41061, Republic of Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health & Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea
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6
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Okabe Y. Development and organization of omental milky spots. Immunol Rev 2024; 324:68-77. [PMID: 38662554 DOI: 10.1111/imr.13337] [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: 12/04/2023] [Accepted: 04/09/2024] [Indexed: 07/23/2024]
Abstract
The milky spots in omentum are atypical lymphoid tissues that play a pivotal role in regulating immune responses in the peritoneal cavity. The milky spots act as central hubs for collecting antigens and particles from the peritoneal cavity, regulating lymphocyte trafficking, promoting the differentiation and self-renewal of immune cells, and supporting the local germinal centre response. In addition, the milky spots exhibit unique developmental characteristics that combine the features of secondary and tertiary lymphoid tissues. These structures are innately programmed to form during foetal development; however, they can also be formed postnatally in response to peritoneal irritation such as inflammation, infection, obesity, or tumour metastasis. In this review, I discuss emerging perspectives on homeostatic development and organization of the milky spots.
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Affiliation(s)
- Yasutaka Okabe
- Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research (CiDER), Osaka University, Osaka, Japan
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7
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Najafi F, Pasdar Y, Nazar MM, Darbandi M. Association between obesity phenotypes and non-alcoholic fatty liver: a large population- based study. BMC Endocr Disord 2024; 24:96. [PMID: 38918729 PMCID: PMC11197192 DOI: 10.1186/s12902-024-01630-4] [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: 03/06/2024] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND The aim of this study was to examine the association between different metabolic obesity phenotypes and the non-alcoholic fatty liver disease (NAFLD). METHODS This cross-sectional analysis utilized data from the baseline phase of the Ravansar non-communicable diseases (RaNCD) cohort study, which involved 8,360 adults. Participants with a Fatty Liver Index (FLI) score of ≥ 60 was classified as having NAFLD. The FLI score was calculated using liver non-invasive markers and anthropometric measurements. Participants were categorized into four phenotypes based on the presence or absence of metabolic syndrome and obesity. Logistic regression analysis was used to evaluate the association of NAFLD and obesity phenotypes. RESULTS According to the FLI index, the prevalence of NAFLD was 39.56%. Participants with FLI scores of ≥ 60 had higher energy intake compared to those in the FLI < 60 group (P = 0.033). In subjects with metabolically unhealthy phenotypes, the level of physical activity was lower compared to those with metabolically healthy phenotypes. The risk of NAFLD in males with the metabolically healthy-obese phenotype increased by 8.92 times (95% CI: 2.20, 15.30), those with the metabolically unhealthy-non-obese phenotype increased by 7.23 times (95% CI: 5.82, 8.99), and those with the metabolically unhealthy-obese phenotype increased by 32.97 times (95% CI: 15.70, 69.22) compared to the metabolically healthy-non-obese phenotype. Similarly, these results were observed in females. CONCLUSION This study demonstrated that the risk of NAFLD is higher in individuals with metabolically healthy/obese, metabolically unhealthy/non-obese, and metabolically unhealthy/obese phenotypes compared to those with non-obese/metabolically healthy phenotypes.
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Affiliation(s)
- Farid Najafi
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yahya Pasdar
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehdi Moradi Nazar
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mitra Darbandi
- Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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8
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Andele PK, Palazzolo S, Corona G, Caligiuri I, Kamensek U, Cemazar M, Canzonieri V, Rizzolio F. Human Omental Mature Adipocytes used as Paclitaxel Reservoir for Cell-Based Therapy in Ovarian Cancer. Adv Healthc Mater 2024; 13:e2304206. [PMID: 38334216 DOI: 10.1002/adhm.202304206] [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: 11/28/2023] [Revised: 01/20/2024] [Indexed: 02/10/2024]
Abstract
Primary human omental adipocytes and ovarian cancer(OC) cells establish a bidirectional communication in which tumor driven lipolysis is induced in adipocytes and the resulting fatty acids are delivered to cancer cells within the tumor microenvironment. Despite meaningful improvement in the treatment of OC, its efficacy is still limited by hydrophobicity and untargeted effects related to chemotherapeutics. Herein, omental adipocytes are firstly used as a reservoir for paclitaxel, named Living Paclitaxel Bullets (LPB) and secondly benefit from the established dialogue between adipocytes and cancer cells to engineer a drug delivery process that target specifically cancer cells. These results show that mature omental adipocytes can successfully uptake paclitaxel and deliver it to OC cells in a transwell coculture based in vitro model. In addition, the efficacy of this proof-of-concept has been demonstrated in vivo and induces a significant inhibition of tumor growth on a xenograft tumor model. The use of mature adipocytes can be suitable for clinical prospection in a cell-based therapy system, due to their mature and differentiated state, to avoid risks related to uncontrolled cell de novo proliferation capacity after the delivery of the antineoplastic drug as observed with other cell types when employed as drug carriers.
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Affiliation(s)
- Pacome K Andele
- Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Venice, 30172, Italy
- Department of Pathology, IRCCS CRO Aviano National Cancer Institute, Aviano, 33081, Italy
| | - Stefano Palazzolo
- Department of Pathology, IRCCS CRO Aviano National Cancer Institute, Aviano, 33081, Italy
| | - Giuseppe Corona
- Immunopathology and Cancer Biomarkers unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, 33081, Italy
| | - Isabella Caligiuri
- Department of Pathology, IRCCS CRO Aviano National Cancer Institute, Aviano, 33081, Italy
| | - Urska Kamensek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
| | - Vincenzo Canzonieri
- Department of Pathology, IRCCS CRO Aviano National Cancer Institute, Aviano, 33081, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, 34127, Italy
| | - Flavio Rizzolio
- Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Venice, 30172, Italy
- Department of Pathology, IRCCS CRO Aviano National Cancer Institute, Aviano, 33081, Italy
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9
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Tang J, Cai X, Liu A, Yu N, Wang S. Association between predicted fat mass, predicted lean mass, predicted percent fat and type 2 diabetes mellitus in Japanese adults: a retrospective study. BMC Endocr Disord 2024; 24:48. [PMID: 38632599 PMCID: PMC11022471 DOI: 10.1186/s12902-024-01579-4] [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: 08/17/2023] [Accepted: 04/12/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is known to have obesity as a risk factor. Body mass index cannot distinguish between lean mass and fat mass. We aimed to examine the association between predicted fat mass, predicted lean mass, predicted percent fat and risk of T2DM in Japanese adults. We also explored whether these three new parameters could predict T2DM better than other obesity markers. METHODS This present study is a secondary data analysis. The study enrolled 20,944 Japanese individuals who participated in the NAGALA medical assessment program between 2004 and 2015. 15,453 participants who are eligible and have complete information were included to our analysis. Through the use of Kaplan-Meier curve, restricted cubic spline and univariate and multivariate Cox regression analysis, the relationship between predicted fat mass, predicted lean mass, predicted percent fat and T2DM risk was examined. The area under the curve method was used to assess the differences between these markers of obesity. RESULTS A total of 373 cases of T2DM occurred over a median time of 5.4 years. In the male group, we found a U-shaped connection between predicted fat mass, predicted lean mass, and T2DM onset (p value, non-linearity < 0.05). A linear relationship was found between predicted percent fat and T2DM onset. The linear relationship was also found in the female group for predicted fat mass, and predicted percent fat. And for women, predicted lean mass was not an independent predictor. The area under the curve (AUC) for predicted fat mass, predicted lean mass, predicted percent fat in men was 0.673 (95%CI: 0.639 ~ 0.707), 0.598 (95%CI: 0.561 ~ 0.635), 0.715 (95%CI: 0.684 ~ 0.745), respectively. In males, WHtR was the strongest predictor (AUC 0.7151, 95%CI: 0.684 ~ 0.746), followed by predicted percent fat (AUC 0.7150, 95%CI: 0.684 ~ 0.745). In the females, WHtR was also the strongest predictor (AUC 0.758, 95%CI: 0.703 ~ 0.813), followed by body mass index (AUC 0.757, 95%CI: 0.704 ~ 0.811) and predicted percent fat (AUC 0.742, 95%CI: 0.687 ~ 0.798). CONCLUSION Predicted fat mass, predicted lean mass, predicted percent fat were strongly connected with an increased risk for developing T2DM in Japanese, particularly in males. WHtR and predicted percent fat had a slightly better discrimination than other common obesity indicators in males. In the females, predicted fat mass and predicted percent fat were associated with T2DM risk, WHtR and body mass index had the slightly higher predictive power.
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Affiliation(s)
- Jiaming Tang
- Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiaohua Cai
- Department of Pharmacy, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, China
| | - Aijie Liu
- Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Nannan Yu
- Department of Geriatrics, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, China.
| | - Shilei Wang
- Department of Anesthesiology, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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10
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Hagberg CE, Spalding KL. White adipocyte dysfunction and obesity-associated pathologies in humans. Nat Rev Mol Cell Biol 2024; 25:270-289. [PMID: 38086922 DOI: 10.1038/s41580-023-00680-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2023] [Indexed: 02/10/2024]
Abstract
The prevalence of obesity and associated chronic diseases continues to increase worldwide, negatively impacting on societies and economies. Whereas the association between excess body weight and increased risk for developing a multitude of diseases is well established, the initiating mechanisms by which weight gain impairs our metabolic health remain surprisingly contested. In order to better address the myriad of disease states associated with obesity, it is essential to understand adipose tissue dysfunction and develop strategies for reinforcing adipocyte health. In this Review we outline the diverse physiological functions and pathological roles of human white adipocytes, examining our current knowledge of why white adipocytes are vital for systemic metabolic control, yet poorly adapted to our current obesogenic environment.
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Affiliation(s)
- Carolina E Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Kirsty L Spalding
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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11
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Pincu Y, Makarenkov N, Tsitrina AA, Rosengarten-Levine M, Haim Y, Yoel U, Liberty IF, Dukhno O, Kukeev I, Blüher M, Veksler-Lublinsky I, Rudich A. Visceral adipocyte size links obesity with dysmetabolism more than fibrosis, and both can be estimated by circulating miRNAs. Obesity (Silver Spring) 2023; 31:2986-2997. [PMID: 37746932 DOI: 10.1002/oby.23899] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE In obesity, adipocyte hypertrophy is detrimental to health, but its' interrelation with fibrosis in the visceral adipose tissue (VAT) depot remains unclear. Because VAT is less accessible via biopsy, biomarkers for VAT quality are needed. The authors hypothesized that VAT adipocyte size and fibrosis are interrelated and can be estimated by circulating microRNAs (circ-miRNAs), contributing to subphenotyping obesity. METHODS Adipocyte size and AT fibrosis were estimated in n = 43 participants (BMI ≥ 30 kg/m2 ). Circ-miRNAs were sequenced (Next Generation Sequencing). RESULTS Participants with above- versus below-median VAT adipocyte area exhibited metabolic dysfunction but lower total and pericellular fibrosis. VAT adipocyte size remained associated with metabolic dysfunction even when controlling for BMI or VAT fibrosis in the entire cohort, as in matched-pairs subanalyses. Next Generation Sequencing uncovered 22 and 6 circ-miRNAs associated with VAT adipocyte size and fibrosis, respectively, with miRNA-130b-3p common to both analyses. The combination of miRNA-130b-3p + miR-150-5p + high-density lipoprotein cholesterol discriminated among those with large versus small VAT adipocytes (receiver operating characteristic-area under the curve: 0.872 [95% CI: 0.747-0.996]), whereas miRNA-130b-3p + miRNA-15a-5p + high-density lipoprotein cholesterol discriminated among those with low and high fibrosis (receiver operating characteristic-area under the curve: 0.823 [95% CI: 0.676-0.97]). CONCLUSIONS These findings suggest that VAT adipocyte size and fibrosis are inversely correlated in obesity and can be estimated by distinct circ-miRNAs, providing a potential tool to subphenotype obesity via a liquid biopsy-like approach to assess VAT health in nonsurgical patients.
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Affiliation(s)
- Yair Pincu
- Department of Health and Exercise Science, University of Oklahoma, Norman, Oklahoma, USA
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Nataly Makarenkov
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Alexandra A Tsitrina
- Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Marina Rosengarten-Levine
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Yulia Haim
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Uri Yoel
- Soroka University Medical Center, Be'er-Sheva, Israel
| | | | - Oleg Dukhno
- Soroka University Medical Center, Be'er-Sheva, Israel
| | - Ivan Kukeev
- Soroka University Medical Center, Be'er-Sheva, Israel
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Isana Veksler-Lublinsky
- Department of Software and Information Systems Engineering, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
| | - Assaf Rudich
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva, Israel
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12
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Shehat MG, Miller MH, Calder AN, Gilbertson TA, Tigno-Aranjuez JT. Dietary fat differentially modulates the response of bone marrow-derived macrophages to TLR4 and NOD2 agonists. Innate Immun 2023; 29:122-131. [PMID: 37545346 PMCID: PMC10468623 DOI: 10.1177/17534259231193926] [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: 06/13/2023] [Revised: 07/15/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023] Open
Abstract
Consumption of diets high in fat has been linked to the development of obesity and related metabolic complications. Such associations originate from the enhanced, chronic, low-grade inflammation mediated by macrophages in response to translocated bacteria, bacterial products, or dietary constituents such as fatty acids (FAs). Nucleotide-binding Oligomerization Domain 2 (NOD2) senses muramyl dipeptide (MDP), a component of bacterial peptidoglycan. The inability to sense peptidoglycan through NOD2 has been demonstrated to lead to dysbiosis, increased bacterial translocation, inflammation and metabolic dysfunction. Currently, it is unknown how consumption of HFDs with different FA compositions might influence NOD2-dependent responses. In this study, we subjected WT mice to a control diet or to HFDs comprised of various ratios of unsaturated to saturated fats and determined the macrophage response to TLR4 and NOD2 agonists. A HFD with equal ratios of saturated and unsaturated fats enhanced subsequent responsiveness of macrophages to LPS but not to MDP. However, a high-unsaturated fat diet (HUFD) or a high-saturated fat diet (HSFD) both decreased the responsiveness to NOD2 agonists compared to that observed in control diet (CD) fed mice. These data suggest that dietary fatty acid composition can influence the subsequent macrophage responsiveness to bacterial products.
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Affiliation(s)
- Michael G. Shehat
- Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Madelyn H. Miller
- Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Ashley N. Calder
- Department of Internal Medicine, University of Central Florida, Orlando, FL, USA
| | | | - Justine T. Tigno-Aranjuez
- Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
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13
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Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol 2023; 20:475-494. [PMID: 36927772 DOI: 10.1038/s41569-023-00847-5] [Citation(s) in RCA: 170] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/08/2023] [Indexed: 03/18/2023]
Abstract
The prevalence of obesity has reached pandemic proportions, and now approximately 25% of adults in Westernized countries have obesity. Recognized as a major health concern, obesity is associated with multiple comorbidities, particularly cardiometabolic disorders. In this Review, we present obesity as an evolutionarily novel condition, summarize the epidemiological evidence on its detrimental cardiometabolic consequences and discuss the major mechanisms involved in the association between obesity and the risk of cardiometabolic diseases. We also examine the role of potential moderators of this association, with evidence for and against the so-called 'metabolically healthy obesity phenotype', the 'fatness but fitness' paradox or the 'obesity paradox'. Although maintenance of optimal cardiometabolic status should be a primary goal in individuals with obesity, losing body weight and, particularly, excess visceral adiposity seems to be necessary to minimize the risk of cardiometabolic diseases.
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Affiliation(s)
- Pedro L Valenzuela
- Physical Activity and Health Research Group (PaHerg), Research Institute of Hospital 12 de Octubre ("i + 12"), Madrid, Spain.
- Department of Systems Biology, University of Alcalá, Alcalá de Henares, Spain.
| | - Pedro Carrera-Bastos
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain
| | | | - Daniel E Lieberman
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Alejandro Santos-Lozano
- Physical Activity and Health Research Group (PaHerg), Research Institute of Hospital 12 de Octubre ("i + 12"), Madrid, Spain
- Department of Health Sciences, European University Miguel de Cervantes, Valladolid, Spain
| | - Alejandro Lucia
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain.
- CIBER of Frailty and Healthy Aging (CIBERFES), Madrid, Spain.
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14
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Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res 2023; 118:3434-3450. [PMID: 35880317 PMCID: PMC10202444 DOI: 10.1093/cvr/cvac120] [Citation(s) in RCA: 183] [Impact Index Per Article: 91.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 02/07/2023] Open
Abstract
Obesity and heart failure with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.
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Affiliation(s)
- Barry A Borlaug
- Department of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA
| | | | - Dalane W Kitzman
- Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | | | - Masaru Obokata
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Oliver J Rider
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK
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15
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The association between visceral adipocyte hypertrophy and NAFLD in subjects with different degrees of adiposity. Hepatol Int 2023; 17:215-224. [PMID: 36071305 DOI: 10.1007/s12072-022-10409-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/12/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate the association between visceral adipocyte hypertrophy and the onset and development of non-alcoholic fatty liver disease (NAFLD) in subjects with different degrees of adiposity. METHODS Omental adipose tissue and liver biopsies were collected from obese subjects. NAFLD was defined according to the NASH Clinical Research Network scoring system. Adipocyte size was measured using pathological section analysis. Adipose tissue insulin resistance (Adipo-IR) was calculated as fasting insulin (pmol/L) × fasting free fatty acid concentration (mmol/L). RESULTS In total, 275 obese patients were enrolled, including 158 females and 58 males with NAFLD. In females, adipocyte size was significantly larger in NAFLD participants as compared to the controls (99.37 ± 14.18 vs. 84.14 ± 12.65 [Formula: see text]m, p < 0.001). Moreover, adipocyte size was larger in females with non-alcoholic steatohepatitis (NASH) as compared to those with non-alcoholic fatty liver (NAFL) (101.45 ± 12.77 vs. 95.79 ± 15.80 [Formula: see text]m, p = 0.015). Mediation analysis showed that adipocyte size impacted the NAFLD activity score through Adipo-IR (b = 0.007 [95% bootstrap CI 0.002, 0.013]). Furthermore, the females were divided into: Q1 (BMI < 32.5 kg/m2), Q2 (BMI 32.5-35.5 kg/m2), Q3 (BMI 35.5-38.8 kg/m2) and Q4 (BMI ≥ 38.8 kg/m2) according to BMI quartiles. Omental adipocyte size was larger in NAFLD subjects in Q1-Q3, but not in Q4. No similar results were observed in males. CONCLUSION For the first time, we reported that visceral adipocyte hypertrophy was associated with the onset and progression of NAFLD in mild to moderate adiposity but not in severe obesity, which may be mediated by adipose tissue insulin resistance.
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16
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Cruz-García EM, Frigolet ME, Canizales-Quinteros S, Gutiérrez-Aguilar R. Differential Gene Expression of Subcutaneous Adipose Tissue among Lean, Obese, and after RYGB (Different Timepoints): Systematic Review and Analysis. Nutrients 2022; 14:nu14224925. [PMID: 36432612 PMCID: PMC9693162 DOI: 10.3390/nu14224925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/23/2022] Open
Abstract
The main roles of adipose tissue include triglycerides storage and adipokine secretion, which regulate energy balance and inflammation status. In obesity, adipocyte dysfunction leads to proinflammatory cytokine production and insulin resistance. Bariatric surgery is the most effective treatment for obesity, the gold-standard technique being Roux-en-Y gastric bypass (RYGB). Since metabolic improvements after RYGB are clear, a better understanding of adipose tissue molecular modifications could be derived from this study. Thus, the aim of this systematic review was to find differentially expressed genes in subcutaneous adipose tissue of lean, obese and post-RYGB (distinct timepoints). To address this objective, publications from 2015-2022 reporting gene expression (candidate genes or transcriptomic approach) of subcutaneous adipose tissue from lean and obese individuals before and after RGYB were searched in PubMed, Elsevier, and Springer Link. Excluded publications were reviews, studies analyzing serum, other types of tissues, or bariatric procedures. A risk-of-bias summary was created for each paper using Robvis, to finally include 17 studies. Differentially expressed genes in post-RYGB vs. obese and lean vs. obese were obtained and the intersection among these groups was used for analysis and gene classification by metabolic pathway. Results showed that the lean state as well as the post-RYGB is similar in terms of increased expression of insulin-sensitizing molecules, inducing lipogenesis over lipolysis and downregulating leukocyte activation, cytokine production and other factors that promote inflammation. Thus, massive weight loss and metabolic improvements after RYGB are accompanied by gene expression modifications reverting the "adipocyte dysfunction" phenomenon observed in obesity conditions.
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Affiliation(s)
- Elena Marisol Cruz-García
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
| | - María E. Frigolet
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genόmica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genόmica (INMEGEN), Mexico City 14610, Mexico
| | - Ruth Gutiérrez-Aguilar
- Laboratorio de Investigación en Enfermedades Metabólicas: Obesidad y Diabetes, Hospital Infantil de México “Federico Gómez”, Mexico City 06720, Mexico
- División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
- Correspondence: ; Tel.: +52-5552289917 (ext. 4509)
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17
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In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity. Int J Mol Sci 2022; 23:ijms231911142. [PMID: 36232443 PMCID: PMC9569927 DOI: 10.3390/ijms231911142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 12/02/2022] Open
Abstract
Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D.
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18
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Börgeson E, Boucher J, Hagberg CE. Of mice and men: Pinpointing species differences in adipose tissue biology. Front Cell Dev Biol 2022; 10:1003118. [PMID: 36187476 PMCID: PMC9521710 DOI: 10.3389/fcell.2022.1003118] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
The prevalence of obesity and metabolic diseases continues to rise, which has led to an increased interest in studying adipose tissue to elucidate underlying disease mechanisms. The use of genetic mouse models has been critical for understanding the role of specific genes for adipose tissue function and the tissue’s impact on other organs. However, mouse adipose tissue displays key differences to human fat, which has led, in some cases, to the emergence of some confounding concepts in the adipose field. Such differences include the depot-specific characteristics of visceral and subcutaneous fat, and divergences in thermogenic fat phenotype between the species. Adipose tissue characteristics may therefore not always be directly compared between species, which is important to consider when setting up new studies or interpreting results. This mini review outlines our current knowledge about the cell biological differences between human and mouse adipocytes and fat depots, highlighting some examples where inadequate knowledge of species-specific differences can lead to confounding results, and presenting plausible anatomic explanations that may underlie the differences. The article thus provides critical insights and guidance for researchers working primarily with only human or mouse fat tissue, and may contribute to new ideas or concepts in the important and evolving field of adipose biology.
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Affiliation(s)
- Emma Börgeson
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Region Vaestra Goetaland, Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jeremie Boucher
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Metabolic Disease, Evotec International GmbH, Göttingen, Germany
| | - Carolina E. Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Carolina E. Hagberg,
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19
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Ibrahim LI, Hajal C, Offeddu GS, Gillrie MR, Kamm RD. Omentum-on-a-chip: A multicellular, vascularized microfluidic model of the human peritoneum for the study of ovarian cancer metastases. Biomaterials 2022; 288:121728. [PMID: 35995621 DOI: 10.1016/j.biomaterials.2022.121728] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 07/30/2022] [Accepted: 08/03/2022] [Indexed: 11/02/2022]
Abstract
Epithelial ovarian cancer has the highest mortality rate of any gynecologic malignancy and most frequently metastasizes to the peritoneal cavity. Intraperitoneal metastases are highly associated with ascites, the pathologic accumulation of peritoneal fluid due to impaired drainage, increased peritoneal permeability, and tumor and stromal cytokine secretion. However, the relationship between ascites, vascular and mesothelial permeability, and ovarian cancer intraperitoneal metastases remains poorly understood. In this study, a vascularized in vitro model of the human peritoneal omentum and ovarian tumor microenvironment (TME) was employed to study stromal cell effects on tumor cell (TC) attachment and growth, as well as TC effects on vascular and mesothelial permeability in models of both early- and late-stage metastases. Control over the number of TCs seeded in the vascularized peritoneum revealed a critical cell density requirement for tumor growth, which was further enhanced by stromal adipocytes and endothelial cells found in the peritoneal omentum. This tumor growth resulted in both a physically-mediated decrease and cytokine-mediated increase in microvascular permeability, emphasizing the important and potentially opposing roles of tumor cells in ascites formation. This system provides a robust platform to elucidate TC-stromal cell interactions during intraperitoneal metastasis of ovarian cancer and presents the first in vitro vascularized model of the human peritoneum and ovarian cancer TME.
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Affiliation(s)
- Lina I Ibrahim
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Cynthia Hajal
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Giovanni S Offeddu
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Mark R Gillrie
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Department of Medicine, University of Calgary, Calgary, AB, T2N4N1, Canada
| | - Roger D Kamm
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
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Adipocyte size, adipose tissue fibrosis, macrophage infiltration and disease risk are different in younger and older individuals with childhood versus adulthood onset obesity. Int J Obes (Lond) 2022; 46:1859-1866. [PMID: 35927468 DOI: 10.1038/s41366-022-01192-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/08/2022]
Abstract
BACKGROUND The timing of obesity onset and age have been shown to affect the risk of obesity-related comorbidities, although the impact of each of these factors on markers of adipose tissue function remains unclear. OBJECTIVE The aim of this study was to determine whether differences in regional adipose tissue characteristics vary with age and age of obesity onset, and whether these differences are associated with the markers of cardiometabolic health. METHODS Adipose tissue samples were obtained from 80 female bariatric surgery candidates who were classified by age of obesity onset and age into 4 groups: (1) younger adults (<40 y) with childhood-onset obesity (<18 y) (Child-Young); (2) younger adults with adulthood-onset obesity (>18 y) (Adult-Young); (3) older adults (>55 y) with childhood-onset obesity (Child-Old); and (4) older adults with adulthood-onset obesity (Adult-Old). Adipocyte diameter, adipose tissue fibrosis, and macrophage infiltration were determined in subcutaneous (SAT) and visceral adipose tissue (VAT). Clinical parameters were obtained from participants' medical records. RESULTS Visceral adipocyte size in the Child-Young group was the smallest of all the groups. Age affected visceral infiltration of M1-like cells with greater percent of M1-like cells in the Adult-Old and Child-Old groups. Though not significant, a stepwise increase in M2-like macrophages in VAT was observed with Adult-Young having the smallest followed by Adult-Old, Child-Young, and Child-Old having the greatest percent of M2-like macrophages. Pericellular fibrosis accumulation in SAT and VAT varied with both age and onset, particularly in the Child-Old group, which had the lowest fibrosis levels. Markers of cardiometabolic health (fasting glucose, glycated hemoglobin, total, HDL- and LDL-cholesterol and triglyceride concentrations) were positively and well-associated with adipose tissue characteristics of the Child-Old group but not of the Adult-Young group. CONCLUSION Older adults with childhood-onset obesity, who had the greatest duration of obesity exposure, were particularly vulnerable to the cardiometabolic effects associated with perturbations in adipose tissue characteristics. These results suggest that age and age of obesity onset may have independent and cumulative effects on obesity pathology.
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Steiner BM, Berry DC. The Regulation of Adipose Tissue Health by Estrogens. Front Endocrinol (Lausanne) 2022; 13:889923. [PMID: 35721736 PMCID: PMC9204494 DOI: 10.3389/fendo.2022.889923] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 12/14/2022] Open
Abstract
Obesity and its' associated metabolic diseases such as type 2 diabetes and cardiometabolic disorders are significant health problems confronting many countries. A major driver for developing obesity and metabolic dysfunction is the uncontrolled expansion of white adipose tissue (WAT). Specifically, the pathophysiological expansion of visceral WAT is often associated with metabolic dysfunction due to changes in adipokine secretion profiles, reduced vascularization, increased fibrosis, and enrichment of pro-inflammatory immune cells. A critical determinate of body fat distribution and WAT health is the sex steroid estrogen. The bioavailability of estrogen appears to favor metabolically healthy subcutaneous fat over visceral fat growth while protecting against changes in metabolic dysfunction. Our review will focus on the role of estrogen on body fat partitioning, WAT homeostasis, adipogenesis, adipocyte progenitor cell (APC) function, and thermogenesis to control WAT health and systemic metabolism.
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Affiliation(s)
| | - Daniel C. Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
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22
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Ott F, Körner C, Werner K, Gericke M, Liebscher I, Lobsien D, Radrezza S, Shevchenko A, Hofmann U, Kratzsch J, Gebhardt R, Berg T, Matz-Soja M. Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21. Cells 2022; 11:cells11101680. [PMID: 35626717 PMCID: PMC9139566 DOI: 10.3390/cells11101680] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 11/24/2022] Open
Abstract
The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.
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Affiliation(s)
- Fritzi Ott
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
- Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Christiane Körner
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
- Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Kim Werner
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
| | - Martin Gericke
- Institute for Anatomy, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany;
| | - Ines Liebscher
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
| | - Donald Lobsien
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, Helios Clinic Erfurt, 99089 Erfurt, Germany;
- Institute for Neuroradiology, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Silvia Radrezza
- Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; (S.R.); (A.S.)
| | - Andrej Shevchenko
- Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; (S.R.); (A.S.)
| | - Ute Hofmann
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany;
| | - Jürgen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany;
| | - Rolf Gebhardt
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
| | - Thomas Berg
- Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Madlen Matz-Soja
- Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany; (F.O.); (C.K.); (K.W.); (I.L.); (R.G.)
- Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Hospital Leipzig, 04103 Leipzig, Germany;
- Correspondence:
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Delaney KZ, Santosa S. Sex differences in regional adipose tissue depots pose different threats for the development of Type 2 diabetes in males and females. Obes Rev 2022; 23:e13393. [PMID: 34985183 DOI: 10.1111/obr.13393] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 01/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) affects males and females disproportionately. In midlife, more males have T2DM than females. The sex difference in T2DM prevalence is, in part, explained by differences in regional adipose tissue characteristics. With obesity, changes to regional adipokine and cytokine release increases the risk of T2DM in both males and females with males having greater levels of TNFα and females having greater levels of leptin, CRP, and adiponectin. Regional immune cell infiltration appears to be pathogenic in both sexes via different routes as males with obesity have greater VAT ATM and a decrease in the protective Treg cells, whereas females have greater SAT ATM and T cells. Lastly, the ability of female adipose tissue to expand all regions through hyperplasia, rather than hypertrophy, protects them against the development of large insulin-resistant adipocytes that dominate male adipose tissue. The objective of this review is to discuss how sex may affect regional differences in adipose tissue characteristics and how these differences may distinguish the development of T2DM in males and females. In doing so, we will show that the origins of T2DM development differ between males and females.
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Affiliation(s)
- Kerri Z Delaney
- Department of Health, Kinesiology and Applied Physiology, Concordia University, Montréal, Québec, Canada.,Metabolism, Obesity and Nutrition Lab, PERFORM Centre, Concordia University, Montréal, Québec, Canada.,Centre de recherche - Axe maladies chroniques, Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Ile-de-Montréal, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
| | - Sylvia Santosa
- Department of Health, Kinesiology and Applied Physiology, Concordia University, Montréal, Québec, Canada.,Metabolism, Obesity and Nutrition Lab, PERFORM Centre, Concordia University, Montréal, Québec, Canada.,Centre de recherche - Axe maladies chroniques, Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Ile-de-Montréal, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
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24
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Regulatory mechanisms of the early phase of white adipocyte differentiation: an overview. Cell Mol Life Sci 2022; 79:139. [PMID: 35184223 PMCID: PMC8858922 DOI: 10.1007/s00018-022-04169-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/10/2022] [Accepted: 01/24/2022] [Indexed: 12/16/2022]
Abstract
The adipose
organ comprises two main fat depots termed white and brown adipose tissues. Adipogenesis is a process leading to newly differentiated adipocytes starting from precursor cells, which requires the contribution of many cellular activities at the genome, transcriptome, proteome, and metabolome levels. The adipogenic program is accomplished through two sequential phases; the first includes events favoring the commitment of adipose tissue stem cells/precursors to preadipocytes, while the second involves mechanisms that allow the achievement of full adipocyte differentiation. While there is a very large literature about the mechanisms involved in terminal adipogenesis, little is known about the first stage of this process. Growing interest in this field is due to the recent identification of adipose tissue precursors, which include a heterogenous cell population within different types of adipose tissue as well as within the same fat depot. In addition, the alteration of the heterogeneity of adipose tissue stem cells and of the mechanisms involved in their commitment have been linked to adipose tissue development defects and hence to the onset/progression of metabolic diseases, such as obesity. For this reason, the characterization of early adipogenic events is crucial to understand the etiology and the evolution of adipogenesis-related pathologies, and to explore the adipose tissue precursors’ potential as future tools for precision medicine.
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25
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Muir LA, Cho KW, Geletka LM, Baker NA, Flesher CG, Ehlers AP, Kaciroti N, Lindsly S, Ronquist S, Rajapakse I, O'Rourke RW, Lumeng CN. Human CD206+ macrophages associate with diabetes and adipose tissue lymphoid clusters. JCI Insight 2022; 7:146563. [PMID: 34990410 PMCID: PMC8855803 DOI: 10.1172/jci.insight.146563] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/15/2021] [Indexed: 12/03/2022] Open
Abstract
Increased adipose tissue macrophages (ATMs) correlate with metabolic dysfunction in humans and are causal in development of insulin resistance in mice. Recent bulk and single-cell transcriptomics studies reveal a wide spectrum of gene expression signatures possible for macrophages that depends on context, but the signatures of human ATM subtypes are not well defined in obesity and diabetes. We profiled 3 prominent ATM subtypes from human adipose tissue in obesity and determined their relationship to type 2 diabetes. Visceral adipose tissue (VAT) and s.c. adipose tissue (SAT) samples were collected from diabetic and nondiabetic obese participants to evaluate cellular content and gene expression. VAT CD206+CD11c- ATMs were increased in diabetic participants, were scavenger receptor-rich with low intracellular lipids, secreted proinflammatory cytokines, and diverged significantly from 2 CD11c+ ATM subtypes, which were lipid-laden, were lipid antigen presenting, and overlapped with monocyte signatures. Furthermore, diabetic VAT was enriched for CD206+CD11c- ATM and inflammatory signatures, scavenger receptors, and MHC II antigen presentation genes. VAT immunostaining found CD206+CD11c- ATMs concentrated in vascularized lymphoid clusters adjacent to CD206-CD11c+ ATMs, while CD206+CD11c+ were distributed between adipocytes. Our results show ATM subtype-specific profiles that uniquely contribute to the phenotypic variation in obesity.
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Affiliation(s)
| | | | | | - Nicki A Baker
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Carmen G Flesher
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Anne P Ehlers
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.,Department of Surgery, Ann Arbor Veterans Affairs Healthcare System, Ann Arbor, Michigan, USA
| | - Niko Kaciroti
- Center for Human Growth and Development, University of Michigan, Ann Arbor, Michigan, USA.,Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA
| | - Stephen Lindsly
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Scott Ronquist
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Indika Rajapakse
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA.,Department of Mathematics and.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Robert W O'Rourke
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.,Department of Surgery, Ann Arbor Veterans Affairs Healthcare System, Ann Arbor, Michigan, USA
| | - Carey N Lumeng
- Department of Pediatrics and.,Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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26
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Ye RZ, Richard G, Gévry N, Tchernof A, Carpentier AC. Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations. Endocr Rev 2022; 43:35-60. [PMID: 34100954 PMCID: PMC8755996 DOI: 10.1210/endrev/bnab018] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Indexed: 11/19/2022]
Abstract
The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders. We also review the numerous mechanistic origins of adipocyte hypertrophy and its relationship with metabolic dysregulation, including changes in adipogenesis, cell senescence, collagen deposition, systemic inflammation, adipokine secretion, and energy balance. To quantify the effect of different FCS measurement methods, we performed statistical analyses across published data while controlling for body mass index, age, and sex.
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Affiliation(s)
- Run Zhou Ye
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Gabriel Richard
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Nicolas Gévry
- Department of Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - André Tchernof
- Québec Heart and Lung Research Institute, Laval University, Québec, Québec, Canada
| | - André C Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada
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27
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Wu Z, Ma Q, Cai S, Sun Y, Zhang Y, Yi J. Rhus chinensis Mill. Fruits Ameliorate Hepatic Glycolipid Metabolism Disorder in Rats Induced by High Fat/High Sugar Diet. Nutrients 2021; 13:nu13124480. [PMID: 34960032 PMCID: PMC8708379 DOI: 10.3390/nu13124480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatic glycolipid metabolism disorder is considered as one of the key factors in the pathogenesis of many chronic diseases. The objective of this study was to investigate the protective effect and underlying mechanisms of Rhus chinensis Mill. fruits against hepatic glycolipid metabolic disorders in rats induced by a high fat/high sugar diet. Results showed that ethanol extract, especially at a dose of 600 mg/kg b.w., could effectively ameliorate glycolipid metabolic disorders in rats. The biochemical indexes, including CAT, GSH and HOMA-IR, were significantly improved by the administration of ethanol extract. Immunohistochemistry and Western blot analysis revealed that ethanol extract up-regulated the expression levels of PI3K/AKT, PPAR-α, and the phosphorylation of IRS1 and AMPK proteins, and down-regulated the expressions of SREBP-1 and FAS proteins in the liver, which are closely related to hepatic glycolipid metabolism. Those findings suggested that R. chinensis Mill. fruits could be developed as functional foods and/or nutraceuticals for preventing or controlling some chronic diseases related to hepatic glycolipid metabolism disorder.
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Affiliation(s)
- Zihuan Wu
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; (Z.W.); (S.C.); (Y.S.); (Y.Z.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China;
| | - Qingqing Ma
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China;
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Shengbao Cai
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; (Z.W.); (S.C.); (Y.S.); (Y.Z.)
| | - Yilin Sun
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; (Z.W.); (S.C.); (Y.S.); (Y.Z.)
| | - Yuanyue Zhang
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; (Z.W.); (S.C.); (Y.S.); (Y.Z.)
| | - Junjie Yi
- Faculty of Food Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China; (Z.W.); (S.C.); (Y.S.); (Y.Z.)
- Correspondence: ; Tel.: +86-15810687441
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Abstract
There are numbers of leukocytes present in peritoneal cavity, not only protecting body cavity from infection but also contributing to peripheral immunity including natural antibody production in circulation. The peritoneal leukocytes compose unique immune compartment, the functions of which cannot be replaced by other lymphoid organs. Atypical lymphoid clusters, called "milky spots", that are located in visceral adipose tissue omentum have the privilege of immune niche in terms of differentiation, recruitment, and activation of peritoneal immunity, yet mechanisms underlying the regulation are underexplored. In this review, I discuss the emerging views of peritoneal immune system in the contexts of its development, organization, and functions.
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Affiliation(s)
- Yasutaka Okabe
- Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center Osaka University, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan.
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Barilla S, Treuter E, Venteclef N. Transcriptional and epigenetic control of adipocyte remodeling during obesity. Obesity (Silver Spring) 2021; 29:2013-2025. [PMID: 34813171 DOI: 10.1002/oby.23248] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/27/2021] [Accepted: 05/07/2021] [Indexed: 01/05/2023]
Abstract
The rising prevalence of obesity over the past decades coincides with the rising awareness that a detailed understanding of both adipose tissue biology and obesity-associated remodeling is crucial for developing therapeutic and preventive strategies. Substantial progress has been made in identifying the signaling pathways and transcriptional networks that orchestrate alterations of adipocyte gene expression linked to diverse phenotypes. Owing to recent advances in epigenomics, we also gained a better appreciation for the fact that different environmental cues can epigenetically reprogram adipocyte fate and function, mainly by altering DNA methylation and histone modification patterns. Intriguingly, it appears that transcription factors and chromatin-modifying coregulator complexes are the key regulatory components that coordinate both signaling-induced transcriptional and epigenetic alterations in adipocytes. In this review, we summarize and discuss current molecular insights into how these alterations and the involved regulatory components trigger adipogenesis and adipose tissue remodeling in response to energy surplus.
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Affiliation(s)
- Serena Barilla
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Eckardt Treuter
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Nicolas Venteclef
- Cordeliers Research Center, Inserm, University of Paris, IMMEDIAB Laboratory, Paris, France
- Inovarion, Paris, France
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30
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Chun KH. Mouse model of the adipose organ: the heterogeneous anatomical characteristics. Arch Pharm Res 2021; 44:857-875. [PMID: 34606058 DOI: 10.1007/s12272-021-01350-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/20/2021] [Indexed: 12/24/2022]
Abstract
Adipose tissue plays a pivotal role in energy storage, hormone secretion, and temperature control. Mammalian adipose tissue is largely divided into white adipose tissue and brown adipose tissue, although recent studies have discovered the existence of beige adipocytes. Adipose tissues are widespread over the whole body and each location shows distinctive metabolic features. Mice are used as a representative experimental model system in metabolic studies due to their numerous advantages. Importantly, the adipose tissues of experimental animals and humans are not perfectly matched, and each adipose tissue exhibits both similar and specific characteristics. Nevertheless, the diversity and characteristics of mouse adipose tissue have not yet been comprehensively summarized. This review summarizes diverse information about the different types of adipose tissue being studied in mouse models. The types and characteristics of adipocytes were described, and each adipose tissue was classified by type, and features such as its distribution, origin, differences from humans, and metabolic characteristics were described. In particular, the distribution of widely studied adipose tissues was illustrated so that researchers can comprehensively grasp its location. Also, the adipose tissues misused or confusingly used among researchers were described. This review will provide researchers with comprehensive information and cautions needed to study adipose tissues in mouse models.
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Affiliation(s)
- Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Inchon, 21936, Republic of Korea.
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31
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Ahmad S, Lyngman LK, Mansouryar M, Dhakal R, Agerholm JS, Khanal P, Nielsen MO. Depot and sex-specific implications for adipose tissue expandability and functional traits in adulthood of late prenatal and early postnatal malnutrition in a precocial sheep model. Physiol Rep 2021; 8:e14600. [PMID: 33038074 PMCID: PMC7547587 DOI: 10.14814/phy2.14600] [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: 05/20/2020] [Revised: 09/10/2020] [Accepted: 09/12/2020] [Indexed: 11/24/2022] Open
Abstract
The aim was to investigate long‐term, tissue and sex‐specific impacts of pre and postnatal malnutrition on expandability and functional traits of different adipose tissues. Twin‐pregnant ewes were fed NORM (~requirements), LOW (50% of NORM) or HIGH (150%/110% of energy/protein) diets the last 6 weeks prepartum (term ~147‐days). Lambs received moderate, low‐fat (CONV) or high‐carbohydrate‐high‐fat (HCHF) diets from 3 days until 6 months of age, and thereafter CONV diet. At 2½ years of age (adulthood), histomorphometric and gene expression patterns were characterized in subcutaneous (SUB), perirenal (PER), mesenteric (MES), and epicardial (EPI) adipose tissues. SUB had sex‐specific (♂<♀) upper‐limits for adipocyte size and cell‐number indices, irrespective of early life nutrition. PER mass and contents of adipocytes were highest in females and HIGH♂, whereas adipocyte cross‐sectional area was lowest in LOW♂. Pre/postnatal nutrition affected gene expression sex‐specifically in SUB + PER, but unrelated to morphological changes. In PER, LOW/LOW♂ were specific targets of gene expression changes. EPI was affected by postnatal nutrition, and HCHF sheep had enlarged adipocytes and upregulated expressions for adipogenic and lipogenic genes. Conclusion: upper‐limits for SUB expandability were markedly lower in males. Major targets for prenatal malnutrition were PER and males. LOW♂ had the lowest PER expandability, whereas HIGH♂ had an adaptive advantage due to increased hypertrophic ability equivalent to females. Fixed expandability in SUB meant PER became a determining factor for MES and ectopic fat deposition, rendering LOW♂ particularly predisposed for obesity‐associated metabolic risks. EPI, in contrast to other tissues, was targeted particularly by early postnatal obesity, resulting in adipocyte hypertrophy in adulthood.
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Affiliation(s)
- Sharmila Ahmad
- Nutrition Research Unit, Department of Animal Science, Aarhus University, Tjele, Denmark
| | - Lise Kirstine Lyngman
- Section of Production, Nutrition and Health, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Morteza Mansouryar
- Section of Production, Nutrition and Health, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Rajan Dhakal
- Section of Production, Nutrition and Health, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Jørgen Steen Agerholm
- Section for Reproduction and Obstetrics, Department of Veterinary Clinical Sciences, University of Copenhagen, Taastrup, Denmark
| | - Prabhat Khanal
- Faculty of Biosciences and Aquaculture, Division for Animal science, Production and Welfare, Nord University, Steinkjer, Norway
| | - Mette Olaf Nielsen
- Nutrition Research Unit, Department of Animal Science, Aarhus University, Tjele, Denmark
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Weems AC, Arno MC, Yu W, Huckstepp RTR, Dove AP. 4D polycarbonates via stereolithography as scaffolds for soft tissue repair. Nat Commun 2021; 12:3771. [PMID: 34226548 PMCID: PMC8257657 DOI: 10.1038/s41467-021-23956-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 05/13/2021] [Indexed: 11/13/2022] Open
Abstract
3D printing has emerged as one of the most promising tools to overcome the processing and morphological limitations of traditional tissue engineering scaffold design. However, there is a need for improved minimally invasive, void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics to ensure consistent tissue support during the healing process. Herein, soft, elastomeric aliphatic polycarbonate-based materials were designed to undergo photopolymerization into supportive soft tissue engineering scaffolds. The 4D nature of the printed scaffolds is manifested in their shape memory properties, which allows them to fill model soft tissue voids without deforming the surrounding material. In vivo, adipocyte lobules were found to infiltrate the surface-eroding scaffold within 2 months, and neovascularization was observed over the same time. Notably, reduced collagen capsule thickness indicates that these scaffolds are highly promising for adipose tissue engineering and repair. Shape memory scaffolds are needed for minimally invasive tissue repair and void filling. Here the authors report on the development of 4D printed polycarbonate-based scaffolds with surface degradation properties which fill voids without deforming tissue and allow for tissue ingrowth with reduced immune response.
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Affiliation(s)
- Andrew C Weems
- School of Chemistry, University of Birmingham, Birmingham, UK.
| | - Maria C Arno
- School of Chemistry, University of Birmingham, Birmingham, UK
| | - Wei Yu
- School of Chemistry, University of Birmingham, Birmingham, UK
| | | | - Andrew P Dove
- School of Chemistry, University of Birmingham, Birmingham, UK.
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33
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Ahmed O, Robinson MW, O'Farrelly C. Inflammatory processes in the liver: divergent roles in homeostasis and pathology. Cell Mol Immunol 2021; 18:1375-1386. [PMID: 33864004 PMCID: PMC8166849 DOI: 10.1038/s41423-021-00639-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
The hepatic immune system is designed to tolerate diverse harmless foreign moieties to maintain homeostasis in the healthy liver. Constant priming and regulation ensure that appropriate immune activation occurs when challenged by pathogens and tissue damage. Failure to accurately discriminate, regulate, or effectively resolve inflammation offsets this balance, jeopardizing overall tissue health resulting from an either overly tolerant or an overactive inflammatory response. Compelling scientific and clinical evidence links dysregulated hepatic immune and inflammatory responses upon sterile injury to several pathological conditions in the liver, particularly nonalcoholic steatohepatitis and ischemia-reperfusion injury. Murine and human studies have described interactions between diverse immune repertoires and nonhematopoietic cell populations in both physiological and pathological activities in the liver, although the molecular mechanisms driving these associations are not clearly understood. Here, we review the dynamic roles of inflammatory mediators in responses to sterile injury in the context of homeostasis and disease, the clinical implications of dysregulated hepatic immune activity and therapeutic developments to regulate liver-specific immunity.
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Affiliation(s)
- Ola Ahmed
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Mark W Robinson
- Department of Biology, Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Cliona O'Farrelly
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
- School of Biochemistry & Immunology, Trinity College Dublin, Dublin 2, Ireland.
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34
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Ahmad S, Drag MH, Salleh SM, Cai Z, Nielsen MO. Transcriptomics analysis of differentially expressed genes in subcutaneous and perirenal adipose tissue of sheep as affected by their pre- and early postnatal malnutrition histories. BMC Genomics 2021; 22:338. [PMID: 33975549 PMCID: PMC8114714 DOI: 10.1186/s12864-021-07672-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/30/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Early life malnutrition is known to target adipose tissue with varying impact depending on timing of the insult. This study aimed to identify differentially expressed genes in subcutaneous (SUB) and perirenal (PER) adipose tissue of 2.5-years old sheep to elucidate the biology underlying differential impacts of late gestation versus early postnatal malnutrition on functional development of adipose tissues. Adipose tissues were obtained from 37 adult sheep born as twins to dams fed either NORM (fulfilling energy and protein requirements), LOW (50% of NORM) or HIGH (110% of protein and 150% of energy requirements) diets in the last 6-weeks of gestation. From day 3 to 6 months of age, lambs were fed high-carbohydrate-high-fat (HCHF) or moderate low-fat (CONV) diets, and thereafter the same moderate low-fat diet. RESULTS The gene expression profile of SUB in the adult sheep was not affected by the pre- or early postnatal nutrition history. In PER, 993 and 186 differentially expressed genes (DEGs) were identified in LOW versus HIGH and NORM, respectively, but no DEG was found between HIGH and NORM. DEGs identified in the mismatched pre- and postnatal nutrition groups LOW-HCHF (101) and HIGH-HCHF (192) were largely downregulated compared to NORM-CONV. Out of 831 DEGs, 595 and 236 were up- and downregulated in HCHF versus CONV, respectively. The functional enrichment analyses revealed that transmembrane (ion) transport activities, motor activities related to cytoskeletal and spermatozoa function (microtubules and the cytoskeletal motor protein, dynein), and responsiveness to the (micro) environmental extracellular conditions, including endocrine and nervous stimuli were enriched in the DEGs of LOW versus HIGH and NORM. We confirmed that mismatched pre- and postnatal feeding was associated with long-term programming of adipose tissue remodeling and immunity-related pathways. In agreement with phenotypic measurements, early postnatal HCHF feeding targeted pathways involved in kidney cell differentiation, and mismatched LOW-HCHF sheep had specific impairments in cholesterol metabolism pathways. CONCLUSIONS Both pre- and postnatal malnutrition differentially programmed (patho-) physiological pathways with implications for adipose functional development associated with metabolic dysfunctions, and PER was a major target.
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Affiliation(s)
- Sharmila Ahmad
- Nutrition Research Unit, Department of Animal Science, Aarhus University, Blichers Alle 20, 8830 Tjele, Denmark
| | - Markus Hodal Drag
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Suraya Mohamad Salleh
- Department of Animal Science, Universiti Putra Malaysia, 43400 Serdang, Selangor Malaysia
- Department of Animal Nutrition and Management, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden
| | - Zexi Cai
- Centre for Quantitative Genetics and Genomics, Aarhus University, Blichers Alle 20, 8830 Tjele, Denmark
| | - Mette Olaf Nielsen
- Nutrition Research Unit, Department of Animal Science, Aarhus University, Blichers Alle 20, 8830 Tjele, Denmark
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35
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Gómez-Zorita S, Queralt M, Vicente MA, González M, Portillo MP. Metabolically healthy obesity and metabolically obese normal weight: a review. J Physiol Biochem 2021; 77:175-189. [PMID: 33704694 DOI: 10.1007/s13105-020-00781-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023]
Abstract
Despite the general relationship between obesity and its co-morbidities, there are both obese individuals who scarcely present the associated pathologies (metabolically healthy obese; MHO) and individuals who present obesity alterations despite having normal weight (metabolically obese normal weight; MONW). It is still difficult to define metabolically MHO and MONW individuals because different classifications have been used in the studies reported. Indeed, different inclusion criteria have been used to discriminate between metabolically healthy and metabolically unhealthy subjects. Due to this and other reasons, such as differences in ethnicity, genetics, and lifestyle of the populations, data concerning the prevalence of MHO and MONW are very variable. The main determinants of MHO are type of growth (hypertrophy or hyperplasia), anatomical location, inflammation of adipose tissue, ectopic fat accumulation, genetic factors, and lifestyles factors. In the case of MONW, the main determinants are genetic background and lifestyle factors. With regard to treatment, it is not clear whether MHO subjects would benefit from traditional lifestyle interventions, based on diet energy restriction and increased physical activity. For MONW subjects, there is still no specialized treatment, and the therapies are the same as those used in obese subjects.
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Affiliation(s)
- Saioa Gómez-Zorita
- Nutrition and Obesity Group. Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU) and Lucio Lascaray Research Institute, Vitoria, Spain. .,BIOARABA Health Research Institute, Vitoria, Spain. .,CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Vitoria, Spain.
| | - Maite Queralt
- Nutrition and Obesity Group. Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU) and Lucio Lascaray Research Institute, Vitoria, Spain
| | - Maria Angeles Vicente
- BIOARABA Health Research Institute, Vitoria, Spain.,Alava University Hospital (Osakidetza), Vitoria, Spain
| | - Marcela González
- Nutrition and Food Science Department, Faculty of Biochemistry and Biological Sciences, National University of Litoral and National Scientific and Technical Research Council (CONICET), 3000, Santa Fe, Argentina
| | - María P Portillo
- Nutrition and Obesity Group. Department of Nutrition and Food Science, University of the Basque Country (UPV/EHU) and Lucio Lascaray Research Institute, Vitoria, Spain.,BIOARABA Health Research Institute, Vitoria, Spain.,CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Vitoria, Spain
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Candi E, Campanelli M, Sica G, Schinzari F, Rovella V, Di Daniele N, Melino J, Tesauro M. Differences in the vascular and metabolic profiles between metabolically healthy and unhealthy obesity. ENDOCRINE AND METABOLIC SCIENCE 2021; 2:100077. [DOI: 10.1016/j.endmts.2020.100077] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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da Cunha de Sá RDC, Simão JDJ, da Silva VS, de Farias TM, Cruz MM, Antraco VJ, Armelin-Correa L, Alonso-Vale MI. Fish Oil Enriched in EPA, but Not in DHA, Reverses the Metabolic Syndrome and Adipocyte Dysfunction Induced by a High-Fat Diet. Nutrients 2021; 13:nu13030754. [PMID: 33652751 PMCID: PMC7996952 DOI: 10.3390/nu13030754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/18/2021] [Accepted: 02/23/2021] [Indexed: 12/31/2022] Open
Abstract
This study aimed to investigate the effects of two commercially available fish oils (FOs) containing different proportions of two omega-3 fatty acids (FA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on the metabolic and endocrine dysfunctions of white adipose tissue resulting from obesity. Male C57BL/6J mice, 8 weeks old, received a control or high-fat diet (CO and HF groups, with 9% and 59% energy from fat, respectively) for 8 weeks. The next 8 weeks, the HF group was subdivided into HF, HF+FO/E (HF+5:1 EPA:DHA), and HF+FO/D (HF+5:1 DHA:EPA). Supplementation was performed by gavage, three times a week. All groups that received the HF diet had lower food and caloric intake, but a higher fat intake, body weight (BW) gain, glucose intolerance, and a significant increase in inguinal (ING), retroperitoneal (RP), and epididymal (EPI) adipose tissues when compared to the CO group. Additionally, HF and HF+FO/D groups showed insulin resistance, adipocyte hypertrophy, increased lipolysis and secretion of TNF-α, resistin and IL-10 adipokines by ING and RP adipocytes, and adiponectin only by the HF+FO/D group in ING adipocytes. All of these effects were completely reversed in the HF+FO/E group, which also showed partial reversion in BW gain and glucose intolerance. Both the HF+FO/E and HF+FO/D groups showed a reduction in ING and RP adipose depots when compared to the HF group, but only HF+FO/E in the EPI depot. HF+FO/E, but not HF+FO/D, was able to prevent the changes triggered by obesity in TNF-α, Il-10, and resistin secretion in ING and RP depots. These results strongly suggest that different EPA:DHA ratios have different impacts on the adipose tissue metabolism, FO being rich in EPA, but not in DHA, and effective in reversing the changes induced by obesity.
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38
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Al-Jaber H, Al-Mansoori L, Elrayess MA. GATA-3 as a Potential Therapeutic Target for Insulin Resistance and Type 2 Diabetes Mellitus. Curr Diabetes Rev 2021; 17:169-179. [PMID: 32628587 DOI: 10.2174/1573399816666200705210417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 11/22/2022]
Abstract
Impaired adipogenesis plays an important role in the development of obesity-associated insulin resistance and type 2 diabetes as it leads to ectopic fat deposition. The anti-adipogenic transcription factor GATA-3 was identified as one of the potential molecular targets responsible for the impairment of adipogenesis. The expression of GATA-3 is higher in insulinresistant obese individuals compared to BMI-matched insulin-sensitive counterparts. Adipose tissue inflammation is a crucial mediator of this process. Hyperglycemia mediates the activation of the immune system, partially through upregulation of GATA- 3, causing exacerbation of the inflammatory state associated with obesity. This review discusses the evidence supporting the inhibition of GATA-3 as a useful therapeutic strategy in obesity-associated insulin resistance and type 2 diabetes, through up-regulation adipogenesis and amelioration of the immune response.
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Affiliation(s)
- Hend Al-Jaber
- Biomedical Research Center, Qatar University, Doha, Qatar
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39
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Healthy Obese Subjects Differ in Chronotype, Sleep Habits, and Adipose Tissue Fatty Acid Composition from Their Non-Healthy Counterparts. Nutrients 2020; 13:nu13010119. [PMID: 33396200 PMCID: PMC7824395 DOI: 10.3390/nu13010119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/22/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is not the same in all individuals and two different phenotypes have been described: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). The aim of this study was to identify factors that explain metabolic health status in a rigorously matched Spanish population. Subcutaneous and visceral fat, adipocyte size and fatty acid composition, cardiometabolic markers in serum, and lifestyle habits were assessed. Higher physical activity in the mornings (Odds Ratio (95% Confidence Interval) (OR (95% CI) = 1.54 (1.09–2.18), p = 0.01)), earlier bedtimes (8:30–10:30 pm) (OR = 2.11 (1.02–4.36), p = 0.04), a complete breakfast (OR = 1.59 (1.07–2.36), p = 0.02), and a greater number of meals per day (4.10 ± 0.05 vs. 3.93 ± 0.05, p < 0.01), were associated with the MHO phenotype. Concentrations of 20:5 n-3 eicosapentaenoic acid (0.26 ± 0.46 vs. 0.10% ± 0.11%, p = 0.04) and 18:3 n-6 gamma-linolenic acid (0.37 ± 0.24 vs. 0.23% ± 0.22%, p = 0.04) in subcutaneous adipocytes were higher and omental adipocyte size (187 094 ± 224 059 µm3 vs. 490 953 ± 229 049 µm3, p = 0.02) was lower in MHO subjects than in those with MUO. Visceral fat area differed between MHO and MUO subjects (135 ± 60 cm2 vs. 178 ± 85 cm2, p = 0.04, respectively). The study highlights specific lifestyle habits that could form part of obesity therapies, not only involving healthier eating habits but also earlier sleeping and exercise patterns.
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40
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Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol 2020; 320:C375-C391. [PMID: 33356944 DOI: 10.1152/ajpcell.00379.2020] [Citation(s) in RCA: 898] [Impact Index Per Article: 179.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.
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Affiliation(s)
- Tatsuo Kawai
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Michael V Autieri
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
| | - Rosario Scalia
- The Cardiovascular Research Center and The Limole Center for Integrated Lymphatic Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
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41
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Abstract
Adipose, or fat, tissue (AT) was once considered an inert tissue that primarily existed to store lipids, and was not historically recognized as an important organ in the regulation and maintenance of health. With the rise of obesity and more rigorous research, AT is now recognized as a highly complex metabolic organ involved in a host of important physiological functions, including glucose homeostasis and a multitude of endocrine capabilities. AT dysfunction has been implicated in several disease states, most notably obesity, metabolic syndrome and type 2 diabetes. The study of AT has provided useful insight in developing strategies to combat these highly prevalent metabolic diseases. This review highlights the major functions of adipose tissue and the consequences that can occur when disruption of these functions leads to systemic metabolic dysfunction.
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Affiliation(s)
- Innocence Harvey
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Anik Boudreau
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Jacqueline M Stephens
- Adipocyte Biology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.,Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
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42
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Liu F, He J, Wang H, Zhu D, Bi Y. Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction. Obes Surg 2020; 30:5086-5100. [PMID: 33021706 PMCID: PMC7719100 DOI: 10.1007/s11695-020-04983-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/30/2022]
Abstract
Emerging evidence highlights that dysfunction of adipose tissue contributes to impaired insulin sensitivity and systemic metabolic deterioration in obese state. Of note, adipocyte hypertrophy serves as a critical event which associates closely with adipose dysfunction. An increase in cell size exacerbates hypoxia and inflammation as well as excessive collagen deposition, finally leading to metabolic dysregulation. Specific mechanisms of adipocyte hypertrophy include dysregulated differentiation and maturation of preadipocytes, enlargement of lipid droplets, and abnormal adipocyte osmolarity sensors. Also, weight loss therapies exert profound influence on adipocyte size. Here, we summarize the critical role of adipocyte hypertrophy in the development of metabolic disturbances. Future studies are required to establish a standard criterion of size measurement to better clarify the impact of adipocyte hypertrophy on changes in metabolic homeostasis.
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Affiliation(s)
- Fangcen Liu
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, China
| | - Jielei He
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hongdong Wang
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, China
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
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43
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Wenderott JK, Flesher CG, Baker NA, Neeley CK, Varban OA, Lumeng CN, Muhammad LN, Yeh C, Green PF, O'Rourke RW. Elucidating nanoscale mechanical properties of diabetic human adipose tissue using atomic force microscopy. Sci Rep 2020; 10:20423. [PMID: 33235234 PMCID: PMC7686328 DOI: 10.1038/s41598-020-77498-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 11/11/2020] [Indexed: 01/07/2023] Open
Abstract
Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue.
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Affiliation(s)
- J K Wenderott
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, 60201, USA
| | - Carmen G Flesher
- Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA
| | - Nicki A Baker
- Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA
| | - Christopher K Neeley
- Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA
| | - Oliver A Varban
- Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA
| | - Carey N Lumeng
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA
- Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Lutfiyya N Muhammad
- Division of Biostatistics, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, USA
| | - Chen Yeh
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, 60201, USA
| | - Peter F Green
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
- National Renewable Energy Laboratory, Golden, CO, 80401, USA.
| | - Robert W O'Rourke
- Department of Surgery, Section of General Surgery, University of Michigan Medical School, 2210 Taubman Center-5343, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5343, USA.
- Department of Surgery, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, 48109, USA.
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Wang L, Hu J, Zhou H. Macrophage and Adipocyte Mitochondrial Dysfunction in Obesity-Induced Metabolic Diseases. World J Mens Health 2020; 39:606-614. [PMID: 33151047 PMCID: PMC8443980 DOI: 10.5534/wjmh.200163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/28/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is one of major health burdens of modern society as it contributes to the growing prevalence of its related comorbidities, such as diabetes, cardiovascular diseases, and some cancers. A series of innate immune cells, especially macrophages, and adipocytes have been implicated in the pathogenesis of obesity. Mitochondrial dysfunction, which is induced by obesity, are critical mediators in initiating inflammation in macrophages and adipocytes, and subsequent systemic insulin resistance. In this review, we discuss new findings on how obesity impairs mitochondrial function in macrophages and adipocytes and how this dysfunction contributes to obesity and its comorbidities. We also summarize drugs that treat metabolic diseases by targeting mitochondrial dysfunction.
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Affiliation(s)
- Liwen Wang
- Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Hunan, China.,National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Hunan, China
| | - Jie Hu
- Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Hunan, China.,National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Hunan, China
| | - Haiyan Zhou
- Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Hunan, China.,National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Hunan, China.
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45
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Perrone MA, Babu Dasari J, Intorcia A, Gualtieri P, Marche M, Di Luozzo M, Merra G, Bernardini S, Romeo F, Sergi D. Phenotypic classification and biochemical profile of obesity for cardiovascular prevention. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2020. [DOI: 10.23736/s0393-3660.20.04259-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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46
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Smith GI, Mittendorfer B, Klein S. Metabolically healthy obesity: facts and fantasies. J Clin Invest 2020; 129:3978-3989. [PMID: 31524630 DOI: 10.1172/jci129186] [Citation(s) in RCA: 391] [Impact Index Per Article: 78.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered "metabolically healthy." However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
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Abstract
A peculiar category of persons with obesity lacking common metabolic disturbances has been depicted and termed as metabolically healthy obesity (MHO). Yet, although MHO patients are free of obesity-associated complications, they might not be entirely precluded from developing cardio-metabolic disorders. Among patients with morbid obesity (MO) who are referred to bariatric surgery, a subset of metabolically healthy MO (MHMO) has been identified and the question arises if these patients would benefit from surgery in terms of mitigating the peril of cardio-metabolic complications. We revisited the pathophysiological mechanisms that define MHO, the currently available data on the cardio-metabolic risk of these patients and finally we reviewed the benefits of bariatric surgery and the urge to better characterize MHMO before submission to surgery.
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Affiliation(s)
- Adriana Florinela Cătoi
- Pathophysiology Department, Faculty of Medicine, 'Iuliu Hațieganu', University of Medicine and Pharmacy Cluj-Napoca Romania, Cluj-Napoca, Romania.
| | - Luca Busetto
- Department of Medicine, University of Padova, Padua, Italy
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Narankiewicz D, Ruiz-Nava J, Buonaiuto V, Ruiz-Moreno MI, López-Carmona MD, Pérez-Belmonte LM, Gómez-Huelgas R, Bernal-López MR. Utility of Liver Function Tests and Fatty Liver Index to Categorize Metabolic Phenotypes in a Mediterranean Population. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17103518. [PMID: 32443453 PMCID: PMC7277926 DOI: 10.3390/ijerph17103518] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 12/21/2022]
Abstract
The aim of this study was to analyze the utility of liver function tests (LFT) and fatty liver index (FLI), a surrogate marker of non-alcoholic fatty liver disease, in the categorization of metabolic phenotypes in a Mediterranean population. A cross-sectional study was performed on a random representative sample of 2233 adults assigned to a health center in Málaga, Spain. The metabolic phenotypes were determined based on body mass index (BMI) categorization and the presence or absence of two or more cardiometabolic abnormalities (high blood pressure, low high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, pre-diabetes) or type 2 diabetes. No difference was observed between metabolically healthy and metabolically abnormal phenotypes on LFT. The mean FLI of the population was 41.1 ± 28.6. FLI was significantly higher (p < 0.001) in the metabolically abnormal phenotypes in all BMI categories. The proportion of individuals with pathological FLI (≥60) was significantly higher in the metabolically abnormal overweight and obese phenotypes (p < 0.001). On a multivariate model adjusted for sex, age, and waist circumference, a significant correlation was found between pathological FLI and metabolically abnormal phenotypes in the overweight and obese BMI categories. Area under the curve (AUC) of FLI as a biomarker was 0.76, 0.74, and 0.72 for the metabolically abnormal normal-weight, overweight, and obese groups, respectively. Liver biochemistry is poorly correlated with metabolic phenotypes. Conversely, a good correlation between FLI, as a marker of non-alcoholic fatty liver disease (NAFLD), and metabolically abnormal phenotypes in all BMI ranges was found. Our study suggests that FLI may be a useful marker for characterizing metabolically abnormal phenotypes in individuals who are overweight or obese.
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Affiliation(s)
- Dariusz Narankiewicz
- Preventive Medicine Department, Virgen de la Victoria University Hospital, 29010 Malaga, Spain;
| | - Josefina Ruiz-Nava
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
| | - Veronica Buonaiuto
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
| | - María Isabel Ruiz-Moreno
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
| | - María Dolores López-Carmona
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
| | - Luis Miguel Pérez-Belmonte
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
| | - Ricardo Gómez-Huelgas
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
- Ciber Fisiopatología de la Obesidad y Nutrición. Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (R.G.-H.); (M.R.B.-L.); Tel.: +34-951-291-169 (R.G.-H.); 34-951-290-346 (M.R.B.-L.); Fax: +34-951-290-006 (R.G.-H.); +34-951-290-302 (M.R.B.-L.)
| | - María Rosa Bernal-López
- Internal Medicine Department, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Malaga, Spain; (J.R.-N.); (V.B.); (M.I.R.-M.); (M.D.L.-C.); (L.M.P.-B.)
- Ciber Fisiopatología de la Obesidad y Nutrición. Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (R.G.-H.); (M.R.B.-L.); Tel.: +34-951-291-169 (R.G.-H.); 34-951-290-346 (M.R.B.-L.); Fax: +34-951-290-006 (R.G.-H.); +34-951-290-302 (M.R.B.-L.)
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Torp Austvoll C, Gallo V, Montag D. Health impact of the Anthropocene: the complex relationship between gut microbiota, epigenetics, and human health, using obesity as an example. Glob Health Epidemiol Genom 2020; 5:e2. [PMID: 32363032 PMCID: PMC7176587 DOI: 10.1017/gheg.2020.2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 12/13/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
The growing prevalence of obesity worldwide poses a public health challenge in the current geological epoch, the Anthropocene. Global changes caused by urbanisation, loss of biodiversity, industrialisation, and land-use are happening alongside microbiota dysbiosis and increasing obesity prevalence. How alterations of the gut microbiota are associated with obesity and the epigenetic mechanism mediating this and other health outcome associations are in the process of being unveiled. Epigenetics is emerging as a key mechanism mediating the interaction between human body and the environment in producing disease. Evidence suggests that the gut microbiota plays a role in obesity as it contributes to different mechanisms, such as metabolism, body weight and composition, inflammatory responses, insulin signalling, and energy extraction from food. Consistently, obese people tend to have a different epigenetic profile compared to non-obese. However, evidence is usually scattered and there is a growing need for a structured framework to conceptualise this complexity and to help shaping complex solutions. In this paper, we propose a framework to analyse the observed associations between the alterations of microbiota and health outcomes and the role of epigenetic mechanisms underlying them using obesity as an example, in the current context of global changes within the Anthropocene.
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Affiliation(s)
- Cecilie Torp Austvoll
- Centre for Primary Care and Public Health, Queen Mary University of London, London, UK
| | - Valentina Gallo
- Centre for Primary Care and Public Health, Queen Mary University of London, London, UK
- London School of Hygiene and Tropical Medicine, London, UK
- School of Public Health, Imperial College London, London, UK
| | - Doreen Montag
- Centre for Primary Care and Public Health, Queen Mary University of London, London, UK
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Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms. Cells 2020; 9:cells9040849. [PMID: 32244542 PMCID: PMC7226803 DOI: 10.3390/cells9040849] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/23/2020] [Accepted: 03/30/2020] [Indexed: 12/22/2022] Open
Abstract
Forkhead box O class proteins (FoxOs) are expressed nearly in all tissues and are involved in different functions such as energy metabolism, redox homeostasis, differentiation, and cell cycle arrest. The plasticity of FoxOs is demonstrated by post-translational modifications that determine diverse levels of transcriptional regulations also controlled by their subcellular localization. Among the different members of the FoxO family, we will focus on FoxO1 in adipose tissue, where it is abundantly expressed and is involved in differentiation and transdifferentiation processes. The capability of FoxO1 to respond differently in dependence of adipose tissue subtype underlines the specific involvement of the transcription factor in energy metabolism and the “browning” process of adipocytes. FoxO1 can localize to nuclear, cytoplasm, and mitochondrial compartments of adipocytes responding to different availability of nutrients and source of reactive oxygen species (ROS). Specifically, fasted state produced-ROS enhance the nuclear activity of FoxO1, triggering the transcription of lipid catabolism and antioxidant response genes. The enhancement of lipid catabolism, in combination with ROS buffering, allows systemic energetic homeostasis and metabolic adaptation of white/beige adipocytes. On the contrary, a fed state induces FoxO1 to accumulate in the cytoplasm, but also in the mitochondria where it affects mitochondrial DNA gene expression. The importance of ROS-mediated signaling in FoxO1 subcellular localization and retrograde communication will be discussed, highlighting key aspects of FoxO1 multifaceted regulation in adipocytes.
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