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Gopalakrishnan V, Kumar C, Robertsen I, Morehouse C, Sparklin B, Khader S, Henry I, Johnson LK, Hertel JK, Christensen H, Sandbu R, Greasley PJ, Sellman BR, Åsberg A, Andersson S, Löfmark RJ, Hjelmesæth J, Karlsson C, Cohen TS. A multi-omics microbiome signature is associated with the benefits of gastric bypass surgery and is differentiated from diet induced weight loss through 2 years of follow-up. Mucosal Immunol 2025:S1933-0219(25)00040-6. [PMID: 40222615 DOI: 10.1016/j.mucimm.2025.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 03/04/2025] [Accepted: 04/07/2025] [Indexed: 04/15/2025]
Abstract
Roux-en-Y gastric bypass (GBP) surgery is an effective treatment for reducing body weight and correcting metabolic dysfunction in individuals with severe obesity. Herein, we characterize the differences between very low energy diet (VLED) and GBP induced weight loss by multi-omic analyses of microbiome and host features in a non-randomized, controlled, single-center study. Eighty-eight participants with severe obesity were recruited into two arms - GBP versus VLED with matching weight loss for 6 weeks and 2-years of follow-up. A dramatic shift in the distribution of gut microbial taxa and their functional capacity was seen in the GBP group at Week 2 after surgery and was sustained through 2 years. Multi-omic analyses were performed after 6 weeks of matching weight loss between the GBP and VLED groups, which pointed to microbiome derived metabolites such as indoxyl sulphate as characterizing the GBP group. We also identified an inverse association between Streptococcus parasanguinis (an oral commensal) and plasma levels of tryptophan and tyrosine. These data have important implications, as they reveal a significant robust restructuring of the microbiome away from a baseline dysbiotic state in the GBP group. Furthermore, multi-omics modelling points to potentially novel mechanistic insights at the intersection of the microbiome and host.
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Affiliation(s)
| | - Chanchal Kumar
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Ida Robertsen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, PO 1068 Blindern, 0316 Oslo, Norway
| | - Christopher Morehouse
- Discovery Microbiome, Early Vaccines and Immune Therapies, Biopharmaceuticals R&D, AstraZeneca, USA
| | - Ben Sparklin
- Discovery Microbiome, Early Vaccines and Immune Therapies, Biopharmaceuticals R&D, AstraZeneca, USA
| | - Shameer Khader
- Data Science and Artificial Intelligence, Biopharmaceuticals R&D, AstraZeneca, USA.
| | - Ian Henry
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Line Kristin Johnson
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, P.O.Box 2168, 3103 Tønsberg, Norway
| | - Jens K Hertel
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, P.O.Box 2168, 3103 Tønsberg, Norway
| | - Hege Christensen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, PO 1068 Blindern, 0316 Oslo, Norway
| | - Rune Sandbu
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, P.O.Box 2168, 3103 Tønsberg, Norway
| | - Peter J Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bret R Sellman
- Discovery Microbiome, Early Vaccines and Immune Therapies, Biopharmaceuticals R&D, AstraZeneca, USA
| | - Anders Åsberg
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, PO 1068 Blindern, 0316 Oslo, Norway; Department of Transplantation Medicine, Oslo University Hospital, P.O.Box 4950 Nydalen 0424 Oslo, Norway
| | - Shalini Andersson
- Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Rasmus Jansson Löfmark
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jøran Hjelmesæth
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, P.O.Box 2168, 3103 Tønsberg, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, 0318 Oslo, Norway
| | - Cecilia Karlsson
- Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Taylor S Cohen
- Late Vaccines and Immune Therapies, Biopharmaceuticals R&D, AstraZeneca, USA.
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Górczyńska-Kosiorz S, Kosiorz M, Dzięgielewska-Gęsiak S. Exploring the Interplay of Genetics and Nutrition in the Rising Epidemic of Obesity and Metabolic Diseases. Nutrients 2024; 16:3562. [PMID: 39458556 PMCID: PMC11510173 DOI: 10.3390/nu16203562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Obesity has become a significant global health issue. This multifaceted condition is influenced by genetic, environmental, and lifestyle factors, significantly influenced by nutrition. Aim: The study's objective is to elucidate the relationship between obesity-related genes, nutrient intake, and the development of obesity and the importance of other metabolic diseases. Methods: A comprehensive literature review spanning the past two decades was conducted to analyze the contributions of genetic variants-including FTO, MC4R, and LEPR-and their associations with dietary habits, highlighting how specific nutrients affect gene expression and obesity risk and how the coexistence of metabolic diseases such as type 2 diabetes and osteoporosis may modulate these factors. Moreover, the role of epigenetic factors, such as dietary patterns that encourage the development of obesity, was explored. Discussion and Conclusions: By understanding the intricate relationships among genetics, nutrients, and obesity development, this study highlights the importance of personalized dietary strategies in managing obesity. Overall, an integrated approach that considers genetic predispositions alongside environmental influences is essential for developing effective prevention and treatment methodologies, ultimately contributing to better health outcomes in diverse populations.
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Affiliation(s)
- Sylwia Górczyńska-Kosiorz
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Matylda Kosiorz
- Students’ Scientific Association by the Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
| | - Sylwia Dzięgielewska-Gęsiak
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 41-902 Bytom, Poland;
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Datta I, Zahoor I, Ata N, Rashid F, Cerghet M, Rattan R, Poisson LM, Giri S. Utility of an Untargeted Metabolomics Approach Using a 2D GC-GC-MS Platform to Distinguish Relapsing and Progressive Multiple Sclerosis. Metabolites 2024; 14:493. [PMID: 39330500 PMCID: PMC11434588 DOI: 10.3390/metabo14090493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/19/2024] [Accepted: 08/28/2024] [Indexed: 09/28/2024] Open
Abstract
Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS, which ultimately progresses to secondary progressive MS (SPMS), while primary progressive MS (PPMS) is a type of MS that worsens gradually over time without remissions. There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course, or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GC-GC-MS platform to identify altered metabolites between RRMS, PPMS, and HS. We profiled 235 metabolites in the serum of patients with RRMS (n = 41), PPMS (n = 31), and HS (n = 91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p < 0.05 (false-discovery rate [FDR] = 0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p < 0.05 (FDR = 0.2). Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p < 0.05): (1) galactose metabolism; (2) amino sugar and nucleotide sugar metabolism; (3) phenylalanine, tyrosine, and tryptophan biosynthesis; and (4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p = 0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p = 0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p = 0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p = 0.03). Overall, our study suggests that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for constructing a metabolite panel for progressive autoimmune diseases such as MS.
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Affiliation(s)
- Indrani Datta
- Department of Public Health Sciences, Henry Ford Health, Detroit, MI 48202, USA
- Department of Neurosurgery, Henry Ford Health, Detroit, MI 48202, USA
| | - Insha Zahoor
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Nasar Ata
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Faraz Rashid
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Mirela Cerghet
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
| | - Ramandeep Rattan
- Women's Health Services, Henry Ford Health, Detroit, MI 48202, USA
| | - Laila M Poisson
- Department of Public Health Sciences, Henry Ford Health, Detroit, MI 48202, USA
| | - Shailendra Giri
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
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Liu X, Zhu L, Liu J, Nie Z, Qiu W. Effect of weight loss interventions on metabolomic signatures in obese children with insulin resistance. Amino Acids 2024; 56:54. [PMID: 39212734 PMCID: PMC11364699 DOI: 10.1007/s00726-024-03409-2] [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: 12/12/2023] [Accepted: 08/05/2024] [Indexed: 09/04/2024]
Abstract
The obesity epidemic among children has become a major public health issue, and the presence of childhood insulin resistance (IR) has been demonstrated prior to the onset of type 2 diabetes mellitus. However, it is unclear whether the metabolomic signature is associated with weight loss interventions in obese children with IR. Thirty-six obese children with IR were selected from the weight loss camp (Shenzhen Sunshine Xing Yada health Technology Co., LTD). Clinical parameters were collected before and after weight loss intervention. Targeted metabolomics of plasma samples was performed by ultra-performance liquid chromatography coupled to the tandem mass spectrometry, and principal component analysis, variable importance in projection, and orthogonal partial least squares discriminant analysis were used to obtain the differentially expressed metabolites. Pathway analysis was conducted with the Homo sapiens (HSA) sets in the Kyoto Encyclopedia of Genes and Genomes. We used machine learning algorithms to obtain the potential biomarkers and Spearman correlation analysis to clarify the association between potential biomarkers and clinical parameters. We found that clinical parameters and metabolite clusters were significantly changed in obese children with IR before and after weight loss intervention. Mechanistically, weight loss intervention significantly changed 61 metabolites in obese children with IR. Furthermore, 12 pathways were significantly changed. Moreover, the machine learning algorithm found 6 important potential biomarkers. In addition, these potential biomarkers were strongly associated with major clinical parameters. These data indicate different metabolomic profiles in obese children with IR after weight loss intervention, providing insights into the clinical parameters and metabolite mechanisms involved in weight loss programs.
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Affiliation(s)
- Xiaoguang Liu
- School of Sport and Health, Guangzhou Sport University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou, China
| | - Lin Zhu
- School of Sport and Health, Guangzhou Sport University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Physical Activity and Health Promotion, Guangzhou Sport University, Guangzhou, China.
| | - Jingxin Liu
- Physical education and sports school, Soochow University, Suzhou, China
| | - Zichen Nie
- Harbin Institute of Technology, Shenzhen, China
| | - Wenjun Qiu
- Zhongkai University of Agriculture and Engineering, Guangzhou, China
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Duarte SG, Donado-Pestana CM, More TH, Rodrigues L, Hiller K, Fiamoncini J. Dry blood spots as a sampling strategy to identify insulin resistance markers during a dietary challenge. GENES & NUTRITION 2024; 19:18. [PMID: 39210266 PMCID: PMC11363552 DOI: 10.1186/s12263-024-00752-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
This study aimed to identify markers of postprandial dysglycemia in the blood of self-described healthy individuals using dry blood spots (DBS) as a sampling strategy. A total of 54 volunteers, including 31 women, participated in a dietary challenge. They consumed a high-fat, high-sugar mixed meal and underwent multiple blood sampling over the course of 150 min to track their postprandial responses. Blood glucose levels were monitored with a portable glucometer and individuals were classified into two groups based on the glucose area under the curve (AUC): High-AUC (H-AUC) and Low-AUC (L-AUC). DBS sampling was performed at the same time points as the assessment of glycemia using Whatman 903 Protein Saver filter paper. A gas chromatography-mass spectrometry-based metabolite profiling was conducted in the DBS samples to assess postprandial changes in blood metabolome. Higher concentrations of metabolites associated with insulin resistance were observed in individuals from the H-AUC group, including sugars and sugar-derived products such as fructose and threonic acid, as well as organic acids and fatty acids such as succinate and stearic acid. Several metabolites detected in the GC-MS analysis remained unidentified, indicating that other markers of hyperglycemia remain to be discovered in DBS. Based on these observations, we demonstrated that the use of DBS as a non-invasive and inexpensive sampling tool allows the identification of metabolites markers of dysglycemia in the postprandial period.
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Affiliation(s)
- Stephany Gonçalves Duarte
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bloco 14, São Paulo, SP, CEP 05508-900, Brazil
| | - Carlos M Donado-Pestana
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bloco 14, São Paulo, SP, CEP 05508-900, Brazil
- Food Research Center - FoRC, University of São Paulo, São Paulo, Brazil
| | - Tushar H More
- Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Braunschweig, Germany
| | - Larissa Rodrigues
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bloco 14, São Paulo, SP, CEP 05508-900, Brazil
| | - Karsten Hiller
- Braunschweig Integrated Centre of Systems Biology, Technische Universität Braunschweig, Braunschweig, Germany
| | - Jarlei Fiamoncini
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 580, Bloco 14, São Paulo, SP, CEP 05508-900, Brazil.
- Food Research Center - FoRC, University of São Paulo, São Paulo, Brazil.
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Benrahla DE, Mohan S, Trickovic M, Castelli FA, Alloul G, Sobngwi A, Abdiche R, Kieser S, Demontant V, Trawinski E, Chollet C, Rodriguez C, Kitagishi H, Fenaille F, Trajkovski M, Motterlini R, Foresti R. An orally active carbon monoxide-releasing molecule enhances beneficial gut microbial species to combat obesity in mice. Redox Biol 2024; 72:103153. [PMID: 38608580 PMCID: PMC11025006 DOI: 10.1016/j.redox.2024.103153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/29/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
Carbon monoxide (CO), a gaseous signaling molecule, has shown promise in preventing body weight gain and metabolic dysfunction induced by high fat diet (HFD), but the mechanisms underlying these effects are largely unknown. An essential component in response to HFD is the gut microbiome, which is significantly altered during obesity and represents a target for developing new therapeutic interventions to fight metabolic diseases. Here, we show that CO delivered to the gut by oral administration with a CO-releasing molecule (CORM-401) accumulates in faeces and enriches a variety of microbial species that were perturbed by a HFD regimen. Notably, Akkermansia muciniphila, which exerts salutary metabolic effects in mice and humans, was strongly depleted by HFD but was the most abundant gut species detected after CORM-401 treatment. Analysis of bacterial transcripts revealed a restoration of microbial functional activity, with partial or full recovery of the Krebs cycle, β-oxidation, respiratory chain and glycolysis. Mice treated with CORM-401 exhibited normalization of several plasma and fecal metabolites that were disrupted by HFD and are dependent on Akkermansia muciniphila's metabolic activity, including indoles and tryptophan derivatives. Finally, CORM-401 treatment led to an improvement in gut morphology as well as reduction of inflammatory markers in colon and cecum and restoration of metabolic profiles in these tissues. Our findings provide therapeutic insights on the efficacy of CO as a potential prebiotic to combat obesity, identifying the gut microbiota as a crucial target for CO-mediated pharmacological activities against metabolic disorders.
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Affiliation(s)
| | - Shruti Mohan
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
| | - Matija Trickovic
- Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Florence Anne Castelli
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, 91191 Gif-sur-Yvette, France
| | - Ghida Alloul
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
| | - Arielle Sobngwi
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
| | - Rosa Abdiche
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France
| | - Silas Kieser
- Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vanessa Demontant
- NGS Platform, Henri Mondor Hospital, AP-HP, and IMRB Institute, University of Paris-Est-Créteil, Créteil, France
| | - Elisabeth Trawinski
- NGS Platform, Henri Mondor Hospital, AP-HP, and IMRB Institute, University of Paris-Est-Créteil, Créteil, France
| | - Céline Chollet
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, 91191 Gif-sur-Yvette, France
| | - Christophe Rodriguez
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France; NGS Platform, Henri Mondor Hospital, AP-HP, and IMRB Institute, University of Paris-Est-Créteil, Créteil, France; Microbiology Unit, Department of Diagnostic, Prevention and Treatment of Infections, Henri Mondor Hospital, AP-HP, University of Paris-Est Créteil, Créteil, France
| | - Hiroaki Kitagishi
- Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto, 610-0321, Japan
| | - François Fenaille
- Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), MetaboHUB, 91191 Gif-sur-Yvette, France
| | - Mirko Trajkovski
- Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | - Roberta Foresti
- University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France.
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Hernandez N, Lokhnygina Y, Ramaker ME, Ilkayeva O, Muehlbauer MJ, Crawford ML, Grant RP, Hsia DS, Jain N, Bain JR, Armstrong S, Newgard CB, Freemark M, Gumus Balikcioglu P. Sex Differences in Branched-chain Amino Acid and Tryptophan Metabolism and Pathogenesis of Youth-onset Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:e1345-e1358. [PMID: 38066593 PMCID: PMC10940256 DOI: 10.1210/clinem/dgad708] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Indexed: 03/16/2024]
Abstract
OBJECTIVES Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth. METHODS Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA. RESULTS Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls. CONCLUSION Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males.
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Affiliation(s)
- Natalie Hernandez
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
| | - Yuliya Lokhnygina
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA
| | - Megan Elizabeth Ramaker
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
| | - Olga Ilkayeva
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael J Muehlbauer
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
| | - Matthew L Crawford
- Department of Research and Development, LabCorp, Burlington, NC 27215, USA
| | - Russell P Grant
- Department of Research and Development, LabCorp, Burlington, NC 27215, USA
| | - Daniel S Hsia
- Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Nina Jain
- Division of Endocrinology, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - James R Bain
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
| | - Sarah Armstrong
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA
- Division of General Pediatrics and Adolescent Health, Duke University Medical Center, Durham, NC 27710, USA
- Department of Family Medicine and Community Health, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University Medical Center, Durham, NC 27710, USA
| | - Christopher B Newgard
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Michael Freemark
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
| | - Pinar Gumus Balikcioglu
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC 27710, USA
- Duke Molecular Physiology Institute (DMPI), Duke University Medical Center, Durham, NC 27701, USA
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27705, USA
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Cremaschi A, De Iorio M, Kothandaraman N, Yap F, Tint MT, Eriksson J. Joint modeling of association networks and longitudinal biomarkers: An application to childhood obesity. Stat Med 2024; 43:1135-1152. [PMID: 38197220 DOI: 10.1002/sim.9994] [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: 02/14/2022] [Revised: 11/30/2023] [Accepted: 12/02/2023] [Indexed: 01/11/2024]
Abstract
The prevalence of chronic non-communicable diseases such as obesity has noticeably increased in the last decade. The study of these diseases in early life is of paramount importance in determining their course in adult life and in supporting clinical interventions. Recently, attention has been drawn to approaches that study the alteration of metabolic pathways in obese children. In this work, we propose a novel joint modeling approach for the analysis of growth biomarkers and metabolite associations, to unveil metabolic pathways related to childhood obesity. Within a Bayesian framework, we flexibly model the temporal evolution of growth trajectories and metabolic associations through the specification of a joint nonparametric random effect distribution, with the main goal of clustering subjects, thus identifying risk sub-groups. Growth profiles as well as patterns of metabolic associations determine the clustering structure. Inclusion of risk factors is straightforward through the specification of a regression term. We demonstrate the proposed approach on data from the Growing Up in Singapore Towards healthy Outcomes cohort study, based in Singapore. Posterior inference is obtained via a tailored MCMC algorithm, involving a nonparametric prior with mixed support. Our analysis has identified potential key pathways in obese children that allow for the exploration of possible molecular mechanisms associated with childhood obesity.
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Affiliation(s)
| | - Maria De Iorio
- Singapore Institute for Clinical Sciences, A*STAR, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Statistical Science, University College London, London, UK
| | | | - Fabian Yap
- Department of Paediatrics, KK Women's and Children's Hospital, Singapore
| | - Mya Thway Tint
- Singapore Institute for Clinical Sciences, A*STAR, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Johan Eriksson
- Singapore Institute for Clinical Sciences, A*STAR, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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9
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India-Aldana S, Yao M, Midya V, Colicino E, Chatzi L, Chu J, Gennings C, Jones DP, Loos RJF, Setiawan VW, Smith MR, Walker RW, Barupal D, Walker DI, Valvi D. PFAS Exposures and the Human Metabolome: A Systematic Review of Epidemiological Studies. CURRENT POLLUTION REPORTS 2023; 9:510-568. [PMID: 37753190 PMCID: PMC10520990 DOI: 10.1007/s40726-023-00269-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/03/2023] [Indexed: 09/28/2023]
Abstract
Purpose of Review There is a growing interest in understanding the health effects of exposure to per- and polyfluoroalkyl substances (PFAS) through the study of the human metabolome. In this systematic review, we aimed to identify consistent findings between PFAS and metabolomic signatures. We conducted a search matching specific keywords that was independently reviewed by two authors on two databases (EMBASE and PubMed) from their inception through July 19, 2022 following PRISMA guidelines. Recent Findings We identified a total of 28 eligible observational studies that evaluated the associations between 31 different PFAS exposures and metabolomics in humans. The most common exposure evaluated was legacy long-chain PFAS. Population sample sizes ranged from 40 to 1,105 participants at different stages across the lifespan. A total of 19 studies used a non-targeted metabolomics approach, 7 used targeted approaches, and 2 included both. The majority of studies were cross-sectional (n = 25), including four with prospective analyses of PFAS measured prior to metabolomics. Summary Most frequently reported associations across studies were observed between PFAS and amino acids, fatty acids, glycerophospholipids, glycerolipids, phosphosphingolipids, bile acids, ceramides, purines, and acylcarnitines. Corresponding metabolic pathways were also altered, including lipid, amino acid, carbohydrate, nucleotide, energy metabolism, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. We found consistent evidence across studies indicating PFAS-induced alterations in lipid and amino acid metabolites, which may be involved in energy and cell membrane disruption.
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Affiliation(s)
- Sandra India-Aldana
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Meizhen Yao
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Vishal Midya
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Elena Colicino
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Leda Chatzi
- Department of Population and Public Health Sciences, Keck
School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jaime Chu
- Department of Pediatrics, Icahn School of Medicine at Mount
Sinai, New York, NY, USA
| | - Chris Gennings
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Dean P. Jones
- Clinical Biomarkers Laboratory, Division of Pulmonary,
Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Ruth J. F. Loos
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
- Charles Bronfman Institute for Personalized Medicine, Icahn
School of Medicine at Mount Sinai, New York, NY, USA
- Faculty of Health and Medical Sciences, Novo Nordisk
Foundation Center for Basic Metabolic Research, University of Copenhagen,
Copenhagen, Denmark
| | - Veronica W. Setiawan
- Department of Population and Public Health Sciences, Keck
School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Mathew Ryan Smith
- Clinical Biomarkers Laboratory, Division of Pulmonary,
Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
- Veterans Affairs Medical Center, Decatur, GA, USA
| | - Ryan W. Walker
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Dinesh Barupal
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Douglas I. Walker
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
| | - Damaskini Valvi
- Department of Environmental Medicine and Public Health,
Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New
York, NY 10029, USA
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10
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Li T, Feng Y, Wang C, Shi T, Abudurexiti A, Zhang M, Gao F. Assessment of causal associations among gut microbiota, metabolites, and celiac disease: a bidirectional Mendelian randomization study. Front Microbiol 2023; 14:1087622. [PMID: 37250054 PMCID: PMC10213403 DOI: 10.3389/fmicb.2023.1087622] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 04/27/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND A growing number of studies have implicated that gut microbial abundance and metabolite concentration alterations are associated with celiac disease (CD). However, the causal relationship underlying these associations is unclear. Here, we used Mendelian randomization (MR) to reveal the causal effect of gut microbiota and metabolites on CD. METHODS Genome-wide association study (GWAS) summary-level data for gut microbiota, metabolites, and CD were extracted from published GWASs. Causal bacterial taxa and metabolites for CD were determined by two-sample MR analyses. The robustness of the results was assessed with sensitivity analyses. Finally, reverse causality was investigated with a reverse MR analysis. RESULTS Genetically, increased genus Bifidobacterium was potentially associated with higher CD risk (odds ratio [OR] = 1.447, 95% confidence interval [CI]: 1.054-1.988, p = 0.022) while phylum Lentisphaerae (OR = 0.798, 95% CI: 0.648-0.983, p = 0.034) and genus Coprobacter (OR = 0.683, 95% CI: 0.531-0.880, p = 0.003) were related to lower CD risk. Moreover, there were suggestive associations between CD and the following seven metabolites: 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 1,6-anhydroglucose, phenylacetylglutamine, tryptophan betaine, 10-undecenoate, and tyrosine. Sensitivity analyses deemed the results reliable without pleiotropy. CONCLUSION We investigated the causal relationships between gut microbiota, metabolites, and CD with two-sample MR. Our findings suggest several novel potential therapeutic targets for CD treatment. Further understanding of the underlying mechanism may provide insights into CD pathogenesis.
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Affiliation(s)
- Ting Li
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Yan Feng
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Chun Wang
- Department of Pathology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Tian Shi
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Adilai Abudurexiti
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Mengxia Zhang
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Feng Gao
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Diseases, Urumqi, Xinjiang, China
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11
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Azab SM, Shanmuganathan M, de Souza RJ, Kroezen Z, Desai D, Williams NC, Morrison KM, Atkinson SA, Teo KK, Azad MB, Simons E, Moraes TJ, Mandhane PJ, Turvey SE, Subbarao P, Britz-McKibbin P, Anand SS. Early sex-dependent differences in metabolic profiles of overweight and adiposity in young children: a cross-sectional analysis. BMC Med 2023; 21:176. [PMID: 37158942 PMCID: PMC10166631 DOI: 10.1186/s12916-023-02886-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/29/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. METHODS Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). RESULTS In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. CONCLUSIONS Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.
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Affiliation(s)
- Sandi M Azab
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Department of Pharmacognosy, Alexandria University, Alexandria, Egypt
- Chanchlani Research Centre, McMaster University, Hamilton, Canada
| | - Meera Shanmuganathan
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Russell J de Souza
- Chanchlani Research Centre, McMaster University, Hamilton, Canada
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada
| | - Zachary Kroezen
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Dipika Desai
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada
| | - Natalie C Williams
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Chanchlani Research Centre, McMaster University, Hamilton, Canada
| | - Katherine M Morrison
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Department of Pediatrics, McMaster University, Hamilton, ON, Canada
| | | | - Koon K Teo
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada
| | - Meghan B Azad
- Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Elinor Simons
- Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Theo J Moraes
- Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
| | - Piush J Mandhane
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Stuart E Turvey
- Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Padmaja Subbarao
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
| | - Philip Britz-McKibbin
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Sonia S Anand
- Department of Medicine, McMaster University, Hamilton, ON, Canada.
- Chanchlani Research Centre, McMaster University, Hamilton, Canada.
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada.
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12
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Gu PS, Su KW, Yeh KW, Huang JL, Lo FS, Chiu CY. Metabolomics Analysis Reveals Molecular Signatures of Metabolic Complexity in Children with Hypercholesterolemia. Nutrients 2023; 15:nu15071726. [PMID: 37049565 PMCID: PMC10096550 DOI: 10.3390/nu15071726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Despite the importance of hypercholesterolemia in children, it is overlooked, and there are currently few metabolomics-based approaches available to understand its molecular mechanisms. Children from a birth cohort had their cholesterol levels measured with the aim of identifying the metabolites for the molecular biological pathways of childhood hypercholesterolemia. One hundred and twenty-five children were enrolled and stratified into three groups according to cholesterol levels (acceptable, <170 mg/dL, n = 42; borderline, 170–200 mg/dL, n = 52; and high, >200 mg/dL, n = 31). Plasma metabolomic profiles were obtained by using 1H-nuclear magnetic resonance (NMR) spectroscopy, and partial least squares-discriminant analysis (PLS-DA) was applied using the MetaboAnalyst 5.0 platform. Metabolites significantly associated with different cholesterol statuses were identified, and random forest classifier models were used to rank the importance of these metabolites. Their associations with serum lipid profile and functional metabolic pathways related to hypercholesterolemia were also assessed. Cholesterol level was significantly positively correlated with LDL-C and Apo-B level, as well as HDL-C and Apo-A1 level separately, whereas HDL-C was negatively correlated with triglyceride level (p < 0.01). Eight metabolites including tyrosine, glutamic acid, ornithine, lysine, alanine, creatinine, oxoglutaric acid, and creatine were significantly associated with the different statuses of cholesterol level. Among them, glutamic acid and tyrosine had the highest importance for different cholesterol statuses using random forest regression models. Carbohydrate and amino acid metabolisms were significantly associated with different cholesterol statuses, with glutamic acid being involved in all amino acid metabolic pathways (FDR-adjusted p < 0.01). Hypercholesterolemia is a significant health concern among children, with up to 25% having high cholesterol levels. Glutamic acid and tyrosine are crucial amino acids in lipid metabolism, with glutamic-acid-related amino acid metabolism playing a significant role in regulating cholesterol levels.
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Affiliation(s)
- Pei-Shin Gu
- Division of Pediatric Endocrinology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Kuan-Wen Su
- Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Kuo-Wei Yeh
- Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Jing-Long Huang
- Department of Pediatrics, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Fu-Sung Lo
- Division of Pediatric Endocrinology, Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chih-Yung Chiu
- Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
- Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8966); Fax: +886-3-3288957
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13
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Childhood Obesity and the Cryptic Language of the Microbiota: Metabolomics’ Upgrading. Metabolites 2023; 13:metabo13030414. [PMID: 36984854 PMCID: PMC10052538 DOI: 10.3390/metabo13030414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/01/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
The growing obesity epidemic in childhood is increasingly concerning for the related physical and psychological consequences, with a significant impact on health care costs in both the short and the long term. Nonetheless, the scientific community has not yet completely clarified the complex metabolic mechanisms underlying body weight alterations. In only a small percentage of cases, obesity is the result of endocrine, monogenic, or syndromic causes, while in much more cases, lifestyle plays a crucial role in obesity development. In this context, the pediatric age appears to be of considerable importance as prevention strategies together with early intervention can represent important therapeutic tools not only to counteract the comorbidities that increasingly affect children but also to hinder the persistence of obesity in adulthood. Although evidence in the literature supporting the alteration of the microbiota as a critical factor in the etiology of obesity is abundant, it is not yet fully defined and understood. However, increasingly clear evidence is emerging regarding the existence of differentiated metabolic profiles in obese children, with characteristic metabolites. The identification of specific pathology-related biomarkers and the elucidation of the altered metabolic pathways would therefore be desirable in order to clarify aspects that are still poorly understood, such as the consequences of the interaction between the host, the diet, and the microbiota. In fact, metabolomics can characterize the biological behavior of a specific individual in response to external stimuli, offering not only an eventual effective screening and prevention strategy but also the possibility of evaluating adherence and response to dietary intervention.
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14
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Woldemariam S, Dorner TE, Wiesinger T, Stein KV. Multi-omics approaches for precision obesity management : Potentials and limitations of omics in precision prevention, treatment and risk reduction of obesity. Wien Klin Wochenschr 2023; 135:113-124. [PMID: 36717394 PMCID: PMC10020295 DOI: 10.1007/s00508-022-02146-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 12/12/2022] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Obesity is a multifactorial chronic disease that cannot be addressed by simply promoting better diets and more physical activity. To date, not a single country has successfully been able to curb the accumulating burden of obesity. One explanation for the lack of progress is that lifestyle intervention programs are traditionally implemented without a comprehensive evaluation of an individual's diagnostic biomarkers. Evidence from genome-wide association studies highlight the importance of genetic and epigenetic factors in the development of obesity and how they in turn affect the transcriptome, metabolites, microbiomes, and proteomes. OBJECTIVE The purpose of this review is to provide an overview of the different types of omics data: genomics, epigenomics, transcriptomics, proteomics, metabolomics and illustrate how a multi-omics approach can be fundamental for the implementation of precision obesity management. RESULTS The different types of omics designs are grouped into two categories, the genotype approach and the phenotype approach. When applied to obesity prevention and management, each omics type could potentially help to detect specific biomarkers in people with risk profiles and guide healthcare professionals and decision makers in developing individualized treatment plans according to the needs of the individual before the onset of obesity. CONCLUSION Integrating multi-omics approaches will enable a paradigm shift from the one size fits all approach towards precision obesity management, i.e. (1) precision prevention of the onset of obesity, (2) precision medicine and tailored treatment of obesity, and (3) precision risk reduction and prevention of secondary diseases related to obesity.
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Affiliation(s)
- Selam Woldemariam
- Karl Landsteiner Institute for Health Promotion Research, 3062, Kirchstetten, Austria
| | - Thomas E Dorner
- Karl Landsteiner Institute for Health Promotion Research, 3062, Kirchstetten, Austria
- Academy for Ageing Research, House of Mercy, 1160, Vienna, Austria
| | - Thomas Wiesinger
- Karl Landsteiner Institute for Health Promotion Research, 3062, Kirchstetten, Austria
| | - Katharina Viktoria Stein
- Karl Landsteiner Institute for Health Promotion Research, 3062, Kirchstetten, Austria.
- Department of Public Health and Primary Care, Leiden University Medical Centre, 2511 DP, The Hague, The Netherlands.
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15
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Rigamonti AE, Frigerio G, Caroli D, De Col A, Cella SG, Sartorio A, Fustinoni S. A Metabolomics-Based Investigation of the Effects of a Short-Term Body Weight Reduction Program in a Cohort of Adolescents with Obesity: A Prospective Interventional Clinical Study. Nutrients 2023; 15:529. [PMID: 36771236 PMCID: PMC9921209 DOI: 10.3390/nu15030529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
Metabolomics applied to assess the response to a body weight reduction program (BWRP) may generate valuable information concerning the biochemical mechanisms/pathways underlying the BWRP-induced cardiometabolic benefits. The aim of the present study was to establish the BWRP-induced changes in the metabolomic profile that characterizes the obese condition. In particular, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to determine a total of 188 endogenous metabolites in the plasma samples of a cohort of 42 adolescents with obesity (female/male = 32/10; age = 15.94 ± 1.33 year; body mass index standard deviation score (BMI SDS) = 2.96 ± 0.46) who underwent a 3-week BWRP, including hypocaloric diet, physical exercise, nutritional education, and psychological support. The BWRP was capable of significantly improving body composition (e.g., BMI SDS, p < 0.0001), glucometabolic homeostasis (e.g., glucose, p < 0.0001), and cardiovascular function (e.g., diastolic blood pressure, p = 0.016). A total of 64 metabolites were significantly reduced after the intervention (at least p < 0.05), including 53 glycerophospholipids (23 PCs ae, 21 PCs aa, and 9 lysoPCs), 7 amino acids (tyrosine, phenylalanine, arginine, citrulline, tryptophan, glutamic acid, and leucine), the biogenic amine kynurenine, 2 sphingomyelins, and (free) carnitine (C0). On the contrary, three metabolites were significantly increased after the intervention (at least p < 0.05)-in particular, glutamine, trans-4-hydroxyproline, and the octadecenoyl-carnitine (C18:1). In conclusion, when administered to adolescents with obesity, a short-term BWRP is capable of changing the metabolomic profile in the plasma.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Gianfranco Frigerio
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue Du Swing, L-4367 Belvaux, Luxembourg
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandra De Col
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, University of Milan, 20129 Milan, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
| | - Silvia Fustinoni
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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16
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Tripolt NJ, Hofer SJ, Pferschy PN, Aziz F, Durand S, Aprahamian F, Nirmalathasan N, Waltenstorfer M, Eisenberg T, Obermayer AMA, Riedl R, Kojzar H, Moser O, Sourij C, Bugger H, Oulhaj A, Pieber TR, Zanker M, Kroemer G, Madeo F, Sourij H. Glucose Metabolism and Metabolomic Changes in Response to Prolonged Fasting in Individuals with Obesity, Type 2 Diabetes and Non-Obese People-A Cohort Trial. Nutrients 2023; 15:511. [PMID: 36771218 PMCID: PMC9921960 DOI: 10.3390/nu15030511] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/21/2023] Open
Abstract
Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.
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Affiliation(s)
- Norbert J. Tripolt
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
| | - Sebastian J. Hofer
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010 Graz, Austria
- BioTechMed Graz, 8010 Graz, Austria
- Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria
- Inserm U1138, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Institut Universitaire de France, Sorbonne Université, Université de Paris, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Peter N. Pferschy
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| | - Faisal Aziz
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
| | - Sylvère Durand
- Inserm U1138, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Institut Universitaire de France, Sorbonne Université, Université de Paris, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Fanny Aprahamian
- Inserm U1138, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Institut Universitaire de France, Sorbonne Université, Université de Paris, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Nitharsshini Nirmalathasan
- Inserm U1138, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Institut Universitaire de France, Sorbonne Université, Université de Paris, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Mara Waltenstorfer
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010 Graz, Austria
| | - Tobias Eisenberg
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010 Graz, Austria
- BioTechMed Graz, 8010 Graz, Austria
- Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria
| | - Anna M. A. Obermayer
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
| | - Regina Riedl
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, 8010 Graz, Austria
| | - Harald Kojzar
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
| | - Othmar Moser
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
- Department of Sport Science, Division of Exercise Physiology and Metabolism, University of Bayreuth, 95440 Bayreuth, Germany
| | - Caren Sourij
- Division of Cardiology, Medical University of Graz, 8010 Graz, Austria
| | - Heiko Bugger
- Division of Cardiology, Medical University of Graz, 8010 Graz, Austria
| | - Abderrahim Oulhaj
- Department of Epidemiology and Population Health, College of Medicine and Health Sciences, Khalifa University Abu Dhabi, Al-Ain P.O. Box 17666, United Arab Emirates
| | - Thomas R. Pieber
- BioTechMed Graz, 8010 Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
| | - Matthias Zanker
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
| | - Guido Kroemer
- Inserm U1138, Equipe Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Institut Universitaire de France, Sorbonne Université, Université de Paris, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
- Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010 Graz, Austria
- BioTechMed Graz, 8010 Graz, Austria
- Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria
| | - Harald Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
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17
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González-Domínguez Á, Armeni M, Savolainen O, Lechuga-Sancho AM, Landberg R, González-Domínguez R. Untargeted Metabolomics Based on Liquid Chromatography-Mass Spectrometry for the Analysis of Plasma and Erythrocyte Samples in Childhood Obesity. Methods Mol Biol 2023; 2571:115-122. [PMID: 36152155 DOI: 10.1007/978-1-0716-2699-3_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The circulating metabolome of human peripheral blood provides valuable information to investigate the molecular mechanisms underlying the development of diseases and to discover candidate biomarkers. In particular, erythrocytes have been proposed as potential systemic indicators of the metabolic and redox status of the organism. To accomplish wide-coverage metabolomics analysis, the combination of complementary analytical techniques is necessary to manage the physicochemical complexity of the human metabolome. Herein, we describe an untargeted metabolomics method to capture the plasmatic and erythroid metabolomes based on ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry, combining reversed-phase liquid chromatography and hydrophilic interaction liquid chromatography. The method provides comprehensive metabolomics fingerprinting of plasma and erythrocyte samples, thereby enabling the elucidation of the distinctive metabolic disturbances behind childhood obesity and associated comorbidities, such as insulin resistance.
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Affiliation(s)
- Álvaro González-Domínguez
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Spain
| | - Marina Armeni
- Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
- Department of Biology and Biological Engineering, Chalmers Mass Spectrometry Infrastructure, Chalmers University of Technology, Gothenburg, Sweden
| | - Otto Savolainen
- Department of Biology and Biological Engineering, Chalmers Mass Spectrometry Infrastructure, Chalmers University of Technology, Gothenburg, Sweden
| | - Alfonso María Lechuga-Sancho
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Spain
- Departamento Materno Infantil y Radiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
- Unidad de Endocrinología Pediátrica y Diabetes, Servicio de Pediatría, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Rikard Landberg
- Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Raúl González-Domínguez
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Spain.
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18
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Gumus Balikcioglu P, Jachthuber Trub C, Balikcioglu M, Ilkayeva O, White PJ, Muehlbauer M, Bain JR, Armstrong S, Freemark M. Branched-chain α-keto acids and glutamate/glutamine: Biomarkers of insulin resistance in childhood obesity. Endocrinol Diabetes Metab 2023; 6:e388. [PMID: 36415168 PMCID: PMC9836245 DOI: 10.1002/edm2.388] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/09/2022] [Accepted: 10/16/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES Insulin resistance (IR) in adolescents with obesity is associated with a sex-dependent metabolic 'signature' comprising the branched-chain amino acids (BCAAs), glutamate/glutamine, C3/C5 acylcarnitines and uric acid. Here, we compared the levels of branched-chain α-keto acids (BCKAs) and glutamate/glutamine, which are the byproducts of BCAA catabolism and uric acid among adolescents with obesity prior to and following a 6-month lifestyle-intervention program. METHODS Fasting plasma samples from 33 adolescents with obesity (16 males, 17 females, aged 12-18 year) were analysed by flow-injection tandem MS and LC-MS/MS. Multiple linear regression models were used to correlate changes in BCKAs, glutamate/glutamine and uric acid with changes in weight and insulin sensitivity as assessed by HOMA-IR, adiponectin and the ratio of triglyceride (TG) to HDL. In predictive models, BCKAs, glutamate/glutamine and uric acid at baseline were used as explanatory variables. RESULTS Baseline BCKAs, glutamate/glutamine and uric acid were higher in males than females despite comparable BMI-metrics. Following lifestyle-intervention, α-keto-β-methylvalerate (α-KMV, a metabolic by product of isoleucine) decreased in males but not in females. The ratio of BCKA/BCAA trended lower in males. In the cohort as a whole, BCKAs correlated positively with the ratio of TG to HDL at baseline and HOMA-IR at 6-month-follow-up. Glutamate/glutamine was positively associated with HOMA-IR at baseline and 6-month-follow-up. A reduction in BCKAs was associated with an increase in adiponectin, and those with higher BCKAs at baseline had higher adiponectin levels at 6-month-follow-up. Interestingly those adolescents with higher uric acid levels at baseline had greater reduction in weight. CONCLUSIONS BCKAs and glutamate/glutamine may serve as biomarkers of IR in adolescents with obesity, and uric acid might serve as a predictor of weight loss in response to lifestyle-intervention. Differential regulation of BCAA catabolism in adolescent males and females implicates critical roles for sex steroids in metabolic homeostasis.
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Affiliation(s)
- Pinar Gumus Balikcioglu
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, North Carolina, USA.,Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA
| | | | - Metin Balikcioglu
- Advanced Analytics Division, SAS Institute Inc, Cary, North Carolina, USA
| | - Olga Ilkayeva
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA.,Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina, USA
| | - Phillip J White
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA.,Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina, USA
| | - Michael Muehlbauer
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA
| | - James R Bain
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA.,Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina, USA
| | - Sarah Armstrong
- Division of General Pediatrics and Adolescent Health, Duke University Medical Center, Durham, North Carolina, USA.,Department of Family Medicine and Community Health, Duke University Medical Center, Durham, North Carolina, USA.,Department of Population Health Sciences, Duke University Medical Center, Durham, North Carolina, USA.,Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA
| | - Michael Freemark
- Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, North Carolina, USA.,Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, USA
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19
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Metabolomics and Lipidomics Signatures of Insulin Resistance and Abdominal Fat Depots in People Living with Obesity. Metabolites 2022; 12:metabo12121272. [PMID: 36557310 PMCID: PMC9781703 DOI: 10.3390/metabo12121272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic clamp with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman’s rank correlation analyses that passed the Benjamini−Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p < 7.2 × 10−4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify diverse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.
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20
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Arjmand B, Ebrahimi Fana S, Ghasemi E, Kazemi A, Ghodssi-Ghassemabadi R, Dehghanbanadaki H, Najjar N, Kakaii A, Forouzanfar K, Nasli-Esfahani E, Farzadfar F, Larijani B, Razi F. Metabolic signatures of insulin resistance in non-diabetic individuals. BMC Endocr Disord 2022; 22:212. [PMID: 36002887 PMCID: PMC9404631 DOI: 10.1186/s12902-022-01130-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 08/18/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Insulin resistance (IR) evolved from excessive energy intake and poor energy expenditure, affecting the patient's quality of life. Amino acid and acylcarnitine metabolomic profiles have identified consistent patterns associated with metabolic disease and insulin sensitivity. Here, we have measured a wide array of metabolites (30 acylcarnitines and 20 amino acids) with the MS/MS and investigated the association of metabolic profile with insulin resistance. METHODS The study population (n = 403) was randomly chosen from non-diabetic participants of the Surveillance of Risk Factors of NCDs in Iran Study (STEPS 2016). STEPS 2016 is a population-based cross-sectional study conducted periodically on adults aged 18-75 years in 30 provinces of Iran. Participants were divided into two groups according to the optimal cut-off point determined by the Youden index of HOMA-IR for the diagnosis of metabolic syndrome. Associations were investigated using regression models adjusted for age, sex, and body mass index (BMI). RESULTS People with high IR were significantly younger, and had higher education level, BMI, waist circumference, FPG, HbA1c, ALT, triglyceride, cholesterol, non-HDL cholesterol, uric acid, and a lower HDL-C level. We observed a strong positive association of serum BCAA (valine and leucine), AAA (tyrosine, tryptophan, and phenylalanine), alanine, and C0 (free carnitine) with IR (HOMA-IR); while C18:1 (oleoyl L-carnitine) was inversely correlated with IR. CONCLUSIONS In the present study, we identified specific metabolites linked to HOMA-IR that improved IR prediction. In summary, our study adds more evidence that a particular metabolomic profile perturbation is associated with metabolic disease and reemphasizes the significance of understanding the biochemistry and physiology which lead to these associations.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran, Iran
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Ebrahimi Fana
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Ghasemi
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ameneh Kazemi
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hojat Dehghanbanadaki
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloufar Najjar
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Kakaii
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Katayoon Forouzanfar
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Nasli-Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshad Farzadfar
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Razi
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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21
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Wei W, Zi T, Yang R, Xu J, Chen Y, Jiang X, Chu X, Yang X, Jiang W. A Newly Developed Indicator of Overeating Saturated Fat Based on Serum Fatty Acids and Amino Acids and Its Association With Incidence of Type 2 Diabetes: Evidence From Two Randomized Controlled Feeding Trials and a Prospective Study. Front Nutr 2022; 9:897375. [PMID: 35774548 PMCID: PMC9237542 DOI: 10.3389/fnut.2022.897375] [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: 03/16/2022] [Accepted: 05/03/2022] [Indexed: 11/29/2022] Open
Abstract
Objective Hyper-caloric intake of saturated fatty acids (SFAs) is common in modern societies, probably contributing to the epidemic of type 2 diabetes mellitus (T2DM). This study conducted two randomized controlled trials (RCTs) for developing a new indicator that can assess the nutritional status and examined its association with incidence of T2DM. Methods In RCT 1, healthy participants were randomly assigned into three groups, namely, control group (n = 40), overfeeding group 1 (100 g butter per day, n = 37), and overfeeding group 2 (120 g butter per day, n = 37). In RCT 2, healthy subjects were randomly assigned into two groups, namely, control group (n = 52) and high-fat group (300-extra kcal/day from diet that was designed by high-fat diet, n = 58). In the prospective cohort, 4,057 participants aged 20–74 years were enrolled and followed up over 5.3 years. Serum profiles of fatty acids and amino acids were measured. Results In RCT 1, serum fatty acids, including C14:0 and C18:0, increased, whereas C18:2, C20:4, C22:5, and C22:6 decreased; serum amino acids, including tyrosine, alanine, and aminobutyric acid, increased, whereas histidine and glycine decreased (p < 0.05). Among these serum fatty acids and amino acids, changes in C14:0, C20:4, tyrosine, histidine, and glycine were also observed in RCT 2. An indicator was developed based on the five fatty acids and amino acids, namely, C14:0 × tyrosine × 1,000/[C20:4 × (glycine + histidine)], and it significantly identified participants in the intervention group with area under the curve (AUC) (95% CI) being 0.85 (0.77–0.92). The indicator was significantly associated with incidence of T2DM in the prospective cohort with HRs (95% CIs) from bottom quartile to top quartile being 1,1.21 (0.82–1.77), 1.60 (1.12–2.30), 2.04 (1.42–2.94). Conclusion The newly developed indicator in RCTs can be used in assessing the nutritional status of hypercaloric intake of SFA and predicting the development of T2DM.
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Affiliation(s)
- Wei Wei
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
- Key Laboratory of Cardiovascular Research, Department of Pharmacology, College of Pharmacy, Ministry of Education, Harbin Medical University, Harbin, China
| | - Tianqi Zi
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
| | - Ruiming Yang
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
| | - Jiaxu Xu
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
| | - Yunyan Chen
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
| | - XiTao Jiang
- College of Engineering, IT and Environment, Charles Darwin University, Darwin, NT, Australia
| | - Xia Chu
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
| | - Xue Yang
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
- *Correspondence: Xue Yang,
| | - Wenbo Jiang
- Department of Nutrition and Food Hygiene, National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Wenbo Jiang,
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22
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The Effect of Polyphenol Extract from Rosa Roxburghii Fruit on Plasma Metabolome and Gut Microbiota in Type 2 Diabetic Mice. Foods 2022; 11:foods11121747. [PMID: 35741945 PMCID: PMC9222671 DOI: 10.3390/foods11121747] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/08/2022] [Indexed: 11/17/2022] Open
Abstract
Rosa roxburghii fruit is an underutilized functional food abundant in polyphenols. Polyphenols have been proved to have antidiabetic effects. This study investigates the effects of Rosa roxburghii fruit polyphenols extract (RPE) on plasma metabolites and gut microbiota composition in streptozotocin (STZ)- and high-fat diet- induced type 2 diabetes using metabolomics and 16S rRNA gene sequencing. The induced diabetic mice were fed with 400 mg/kg body weight RPE for 8 weeks. RPE demonstrated hypoglycemic, hypolipidemic, and anti-inflammatory effects. Colonic oxidative stress biomarkers were also lowered by RPE. Besides, RPE decreased plasma ceramides and tyrosine levels and increased carnitine and phosphatidylinositols levels, indicating improved insulin resistance, lipid metabolism, and immune response. Furthermore, RPE decreased abundances of Lachnospiraceae and Rikenellaceae and increased abundances of Erysipelotrichaceae and Faecalibaculum. Metabolic function prediction of the gut microbiota by PICRUSt demonstrated that RPE downregulated the phosphotransferase system. Taken together, these findings demonstrated that RPE has the potential to prevent type 2 diabetes by regulating the plasma metabolites and gut microbes.
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23
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Chatterjee A, Sakallioglu IT, Murthy D, Kosmacek EA, Singh PK, McDonald JT, Powers R, Oberley-Deegan RE. MnTE-2-PyP protects fibroblast mitochondria from hyperglycemia and radiation exposure. Redox Biol 2022; 52:102301. [PMID: 35358851 PMCID: PMC8967707 DOI: 10.1016/j.redox.2022.102301] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/04/2022] [Accepted: 03/21/2022] [Indexed: 11/20/2022] Open
Abstract
Radiation is a common anticancer therapy for prostate cancer, which transforms tumor-associated normal fibroblasts to myofibroblasts, resulting in fibrosis. Oxidative stress caused by radiation-mediated mitochondrial damage is one of the major contributors to fibrosis. As diabetics are oxidatively stressed, radiation-mediated reactive oxygen species cause severe treatment failure, treatment-related side effects, and significantly reduced survival for diabetic prostate cancer patients as compared to non-diabetic prostate cancer patients. Hyperglycemia and enhanced mitochondrial damage significantly contribute to oxidative damage and disease progression after radiation therapy among diabetic prostate cancer patients. Therefore, reduction of mitochondrial damage in normal prostate fibroblasts after radiation should improve the overall clinical state of diabetic prostate cancer patients. We previously reported that MnTE-2-PyP, a manganese porphyrin, reduces oxidative damage in irradiated hyperglycemic prostate fibroblasts by scavenging superoxide and activating NRF2. In the current study, we have investigated the potential role of MnTE-2-PyP to protect mitochondrial health in irradiated hyperglycemic prostate fibroblasts. This study revealed that hyperglycemia and radiation increased mitochondrial ROS via blocking the mitochondrial electron transport chain, altered mitochondrial dynamics, and reduced mitochondrial biogenesis. Increased mitochondrial damage preceeded an increase in myofibroblast differentiation. MnTE-2-PyP reduced myofibroblast differentiation, improved mitochondrial health by releasing the block on the mitochondrial electron transport chain, enhanced ATP production efficiency, and restored mitochondrial dynamics and metabolism in the irradiated-hyperglycemic prostate fibroblasts. Therefore, we are proposing that one of the mechanisms that MnTE-2-PyP protects prostate fibroblasts from irradiation and hyperglycemia-mediated damage is by protecting the mitochondrial health in diabetic prostate cancer patients.
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Affiliation(s)
- Arpita Chatterjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Isin T Sakallioglu
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA
| | - Divya Murthy
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Elizabeth A Kosmacek
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pankaj K Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - J Tyson McDonald
- Department of Physics & Cancer Research Center, Hampton University, Hampton, VA, 23668, USA
| | - Robert Powers
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA; Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304, USA
| | - Rebecca E Oberley-Deegan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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24
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Yan S, Chen J, Zhu L, Guo T, Qin D, Hu Z, Han S, Zhou Y, Akan OD, Wang J, Luo F, Lin Q. Oryzanol Attenuates High Fat and Cholesterol Diet-Induced Hyperlipidemia by Regulating the Gut Microbiome and Amino Acid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:6429-6443. [PMID: 35587527 DOI: 10.1021/acs.jafc.2c00885] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hyperlipidemia is intricately associated with the dysregulation of gut microbiota and host metabolomes. This study explored the antihyperlipidemic function of oryzanol and investigated whether the function of oryzanol affected the gut microbiome and its related metabolites. Hamsters were fed a standard diet (Control) and a high fat and cholesterol (HFCD) diet with or without oryzanol, separately. Our results showed that oryzanol significantly decreased HFCD-induced fat accumulation, serum total cholesterol, low-density lipoprotein cholesterol (LDL-c), LDL-c/HDL-c ratio, triglyceride, and liver steatohepatitis, attenuated HFCD-induced gut microbiota alterations, and altered amino acid concentrations in feces and the liver. We investigated the role of the gut microbiota in the observed beneficial effects; the protective effects of oryzanol were partly diminished by suppressing the gut bacteria of hamsters after using antibiotics. A fecal microbiota transplantation experiment was carried out by transplanting the feces from HFCD group hamsters or hamsters given oryzanol supplementation (as a donor hamster). Our results showed that administering the fecal liquid from oryzanol-treated hamsters attenuated HFCD-induced hyperlipidemia, significantly decreased the abundance of norank_f__Erysipelotrichaceae, norank_f__Eubacteriaceae, and norank_f__Oscillospiraceae and the concentration of tyrosine. These outcomes are significantly positively correlated with serum lipid concentration. This study illustrated that gut microbiota is the target of oryzanol in the antihyperlipidemic effect.
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Affiliation(s)
- Sisi Yan
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Jihong Chen
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Lingfeng Zhu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Tianyi Guo
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Dandan Qin
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Zuomin Hu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Shuai Han
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Yaping Zhou
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Otobang Donald Akan
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Ji Wang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
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Paapstel K, Kals J. Metabolomics of Arterial Stiffness. Metabolites 2022; 12:370. [PMID: 35629874 PMCID: PMC9146333 DOI: 10.3390/metabo12050370] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/15/2022] [Accepted: 04/18/2022] [Indexed: 12/18/2022] Open
Abstract
Arterial stiffness (AS) is one of the earliest detectable signs of structural and functional alterations of the vessel wall and an independent predictor of cardiovascular events and death. The emerging field of metabolomics can be utilized to detect a wide spectrum of intermediates and products of metabolism in body fluids that can be involved in the pathogenesis of AS. Research over the past decade has reinforced this idea by linking AS to circulating acylcarnitines, glycerophospholipids, sphingolipids, and amino acids, among other metabolite species. Some of these metabolites influence AS through traditional cardiovascular risk factors (e.g., high blood pressure, high blood cholesterol, diabetes, smoking), while others seem to act independently through both known and unknown pathophysiological mechanisms. We propose the term 'arteriometabolomics' to indicate the research that applies metabolomics methods to study AS. The 'arteriometabolomics' approach has the potential to allow more personalized cardiovascular risk stratification, disease monitoring, and treatment selection. One of its major goals is to uncover the causal metabolic pathways of AS. Such pathways could represent valuable treatment targets in vascular ageing.
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Affiliation(s)
- Kaido Paapstel
- Endothelial Research Centre, University of Tartu, 8 Puusepa Street, 51014 Tartu, Estonia;
- Department of Cardiology, Institute of Clinical Medicine, University of Tartu, 8 Puusepa Street, 51014 Tartu, Estonia
- Heart Clinic, Tartu University Hospital, 8 Puusepa Street, 51014 Tartu, Estonia
| | - Jaak Kals
- Endothelial Research Centre, University of Tartu, 8 Puusepa Street, 51014 Tartu, Estonia;
- Department of Surgery, Institute of Clinical Medicine, University of Tartu, 8 Puusepa Street, 51014 Tartu, Estonia
- Surgery Clinic, Tartu University Hospital, 8 Puusepa Street, 51014 Tartu, Estonia
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Genomics and Translational Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia
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Murthy VL, Nayor M, Carnethon M, Reis JP, Lloyd-Jones D, Allen NB, Kitchen R, Piaggi P, Steffen LM, Vasan RS, Freedman JE, Clish CB, Shah RV. Circulating metabolite profile in young adulthood identifies long-term diabetes susceptibility: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetologia 2022; 65:657-674. [PMID: 35041022 PMCID: PMC8969893 DOI: 10.1007/s00125-021-05641-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/10/2021] [Indexed: 12/19/2022]
Abstract
AIMS/HYPOTHESIS The aim of this work was to define metabolic correlates and pathways of diabetes pathogenesis in young adults during a subclinical latent phase of diabetes development. METHODS We studied 2083 young adults of Black and White ethnicity in the prospective observational cohort Coronary Artery Risk Development in Young Adults (CARDIA) study (mean ± SD age 32.1 ± 3.6 years; 43.9% women; 42.7% Black; mean ± SD BMI 25.6 ± 4.9 kg/m2) and 1797 Framingham Heart Study (FHS) participants (mean ± SD age 54.7 ± 9.7 years; 52.1% women; mean ± SD BMI 27.4 ± 4.8 kg/m2), examining the association of comprehensive metabolite profiles with endophenotypes of diabetes susceptibility (adipose and muscle tissue phenotypes and systemic inflammation). Statistical learning techniques and Cox regression were used to identify metabolite signatures of incident diabetes over a median of nearly two decades of follow-up across both cohorts. RESULTS We identified known and novel metabolites associated with endophenotypes that delineate the complex pathophysiological architecture of diabetes, spanning mechanisms of muscle insulin resistance, inflammatory lipid signalling and beta cell metabolism (e.g. bioactive lipids, amino acids and microbe- and diet-derived metabolites). Integrating endophenotypes of diabetes susceptibility with the metabolome generated two multi-parametric metabolite scores, one of which (a proinflammatory adiposity score) was associated with incident diabetes across the life course in participants from both the CARDIA study (young adults; HR in a fully adjusted model 2.10 [95% CI 1.72, 2.55], p<0.0001) and FHS (middle-aged and older adults; HR 1.33 [95% CI 1.14, 1.56], p=0.0004). A metabolite score based on the outcome of diabetes was strongly related to diabetes in CARDIA study participants (fully adjusted HR 3.41 [95% CI 2.85, 4.07], p<0.0001) but not in the older FHS population (HR 1.15 [95% CI 0.99, 1.33], p=0.07). CONCLUSIONS/INTERPRETATION Selected metabolic abnormalities in young adulthood identify individuals with heightened diabetes risk independent of race, sex and traditional diabetes risk factors. These signatures replicate across the life course.
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Affiliation(s)
- Venkatesh L Murthy
- Department of Medicine and Radiology, University of Michigan, Ann Arbor, MI, USA.
| | - Matthew Nayor
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | | | - Jared P Reis
- National Heart, Lung, and Blood Institute, Bethesda, MD, USA
| | | | | | - Robert Kitchen
- Simches Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Paolo Piaggi
- Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Lyn M Steffen
- University of Minnesota School of Public Health, Minneapolis, MN, USA
| | - Ramachandran S Vasan
- Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA
- Framingham Heart Study, Framingham, MA, USA
| | - Jane E Freedman
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Clary B Clish
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Ravi V Shah
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
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Amino Acid-Related Metabolic Signature in Obese Children and Adolescents. Nutrients 2022; 14:nu14071454. [PMID: 35406066 PMCID: PMC9003189 DOI: 10.3390/nu14071454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
The growing interest in metabolomics has spread to the search for suitable predictive biomarkers for complications related to the emerging issue of pediatric obesity and its related cardiovascular risk and metabolic alteration. Indeed, several studies have investigated the association between metabolic disorders and amino acids, in particular branched-chain amino acids (BCAAs). We have performed a revision of the literature to assess the role of BCAAs in children and adolescents' metabolism, focusing on the molecular pathways involved. We searched on Pubmed/Medline, including articles published until February 2022. The results have shown that plasmatic levels of BCAAs are impaired already in obese children and adolescents. The relationship between BCAAs, obesity and the related metabolic disorders is explained on one side by the activation of the mTORC1 complex-that may promote insulin resistance-and on the other, by the accumulation of toxic metabolites, which may lead to mitochondrial dysfunction, stress kinase activation and damage of pancreatic cells. These compounds may help in the precocious identification of many complications of pediatric obesity. However, further studies are still needed to better assess if BCAAs may be used to screen these conditions and if any other metabolomic compound may be useful to achieve this goal.
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28
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Chen X, Ye J, Lei H, Wang C. Novel Potential Diagnostic Serum Biomarkers of Metabolomics in Osteoarticular Tuberculosis Patients: A Preliminary Study. Front Cell Infect Microbiol 2022; 12:827528. [PMID: 35402287 PMCID: PMC8992656 DOI: 10.3389/fcimb.2022.827528] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/21/2022] [Indexed: 11/17/2022] Open
Abstract
Osteoarticular tuberculosis is one of the extrapulmonary tuberculosis, which is mainly caused by direct infection of Mycobacterium tuberculosis or secondary infection of tuberculosis in other parts. Due to the low specificity of the current detection method, it is leading to a high misdiagnosis rate and subsequently affecting the follow-up treatment and prognosis. Metabolomics is mainly used to study the changes of the body’s metabolites in different states, so it can serve as an important means in the discovery of disease-related metabolic biomarkers and the corresponding mechanism research. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to detect and analyze metabolites in the serum with osteoarticular tuberculosis patients, disease controls, and healthy controls to find novel metabolic biomarkers that could be used in the diagnosis of osteoarticular tuberculosis. Our results showed that 68 differential metabolites (p<0.05, fold change>1.0) were obtained in osteoarticular tuberculosis serum after statistical analysis. Then, through the evaluation of diagnostic efficacy, PC[o-16:1(9Z)/18:0], PC[20:4(8Z,11Z,14Z,17Z)/18:0], PC[18:0/22:5(4Z,7Z,10Z,13Z,16Z)], SM(d18:1/20:0), and SM[d18:1/18:1(11Z)] were found as potential biomarkers with high diagnostic efficacy. Using bioinformatics analysis, we further found that these metabolites share many lipid metabolic signaling pathways, such as choline metabolism, sphingolipid signaling, retrograde endocannabinoid signaling, and sphingolipid and glycerophospholipid metabolism; these results suggest that lipid metabolism plays an important role in the pathological process of tuberculosis. This study can provide certain reference value for the study of metabolic biomarkers of osteoarticular tuberculosis and the mechanism of lipid metabolism in osteoarticular tuberculosis and even other tuberculosis diseases.
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Affiliation(s)
- Ximeng Chen
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- Department of Clinical Laboratory Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Jingyun Ye
- Department of Clinical Laboratory Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Hong Lei
- Department of Clinical Laboratory Medicine, The Eighth Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Chengbin Wang, ; Hong Lei,
| | - Chengbin Wang
- Department of Clinical Laboratory Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Chengbin Wang, ; Hong Lei,
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Azab SM, de Souza RJ, Lamri A, Shanmuganathan M, Kroezen Z, Schulze KM, Desai D, Williams NC, Morrison KM, Atkinson SA, Teo KK, Britz-McKibbin P, Anand SS. Metabolite profiles and the risk of metabolic syndrome in early childhood: a case-control study. BMC Med 2021; 19:292. [PMID: 34823524 PMCID: PMC8616718 DOI: 10.1186/s12916-021-02162-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Defining the metabolic syndrome (MetS) in children remains challenging. Furthermore, a dichotomous MetS diagnosis can limit the power to study associations. We sought to characterize the serum metabolite signature of the MetS in early childhood using high-throughput metabolomic technologies that allow comprehensive profiling of metabolic status from a biospecimen. METHODS In the Family Atherosclerosis Monitoring In earLY life (FAMILY) prospective birth cohort study, we selected 228 cases of MetS and 228 matched controls among children age 5 years. In addition, a continuous MetS risk score was calculated for all 456 participants. Comprehensive metabolite profiling was performed on fasting serum samples using multisegment injection-capillary electrophoresis-mass spectrometry. Multivariable regression models were applied to test metabolite associations with MetS adjusting for covariates of screen time, diet quality, physical activity, night sleep, socioeconomic status, age, and sex. RESULTS Compared to controls, thirteen serum metabolites were identified in MetS cases when using multivariable regression models, and using the quantitative MetS score, an additional eight metabolites were identified. These included metabolites associated with gluconeogenesis (glucose (odds ratio (OR) 1.55 [95% CI 1.25-1.93]) and glutamine/glutamate ratio (OR 0.82 [95% CI 0.67-1.00])) and the alanine-glucose cycle (alanine (OR 1.41 [95% CI 1.16-1.73])), amino acids metabolism (tyrosine (OR 1.33 [95% CI 1.10-1.63]), threonine (OR 1.24 [95% CI 1.02-1.51]), monomethylarginine (OR 1.33 [95% CI 1.09-1.64]) and lysine (OR 1.23 [95% CI 1.01-1.50])), tryptophan metabolism (tryptophan (OR 0.78 [95% CI 0.64-0.95])), and fatty acids metabolism (carnitine (OR 1.24 [95% CI 1.02-1.51])). The quantitative MetS risk score was more powerful than the dichotomous outcome in consistently detecting this metabolite signature. CONCLUSIONS A distinct metabolite signature of pediatric MetS is detectable in children as young as 5 years old and may improve risk assessment at early stages of development.
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Affiliation(s)
- Sandi M Azab
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Russell J de Souza
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton, ON, Canada
| | - Amel Lamri
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton, ON, Canada
| | - Meera Shanmuganathan
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Zachary Kroezen
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | | | - Dipika Desai
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton, ON, Canada
| | | | - Katherine M Morrison
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton, ON, Canada
- Department of Pediatrics, McMaster University, Hamilton, ON, Canada
| | | | - Koon K Teo
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- Population Health Research Institute, Hamilton, ON, Canada
| | - Philip Britz-McKibbin
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada
| | - Sonia S Anand
- Department of Medicine, McMaster University, Hamilton, ON, Canada.
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.
- Population Health Research Institute, Hamilton, ON, Canada.
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Circulating amino acids as fingerprints of visceral adipose tissue independent of insulin resistance: a targeted metabolomic research in women. REV ROMANA MED LAB 2021. [DOI: 10.2478/rrlm-2021-0033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Introduction: Although obesity and its biomarkers have been intensively studied, little is known about the metabolomic signature of visceral adiposity independent of insulin resistance that frequently accompanies increased levels of visceral fat. Our study aimed to investigate specific changes in amino acid (AA) levels as biomarkers of increased visceral adiposity independent of insulin resistance, in healthy subjects.
Methods: Forty-two adult women were included in this cross-sectional study. Serum samples were analyzed by AAs targeted metabolomics according to their visceral fat area (<100 cm2 and ≥100 cm2).
Results: By corrected t-test and supervised partial least-squares discriminant analysis (PLS-DA) we identified 4 AAs that were significantly higher in the group with higher visceral fat: proline (variable importance in the projection [VIP] predicted value: 1.97), tyrosine (VIP: 2.21), cysteine (VIP: 1.19), isoleucine (VIP: 1.04; p-values <0.05). Also, glycine was significantly lower in the group with higher visceral fat (VIP: 1.65; p-value <0.05). All AAs identified were associated with visceral fat independent of homeo-static model assessment for insulin resistance (p-value for regression coefficients <0.05).
Conclusion: Metabolic pathways that might be disrupted in persons with increased visceral fat are phenylalanine, tyrosine, and tryptophan biosynthesis; tyrosine metabolism; glycine, serine, and threonine metabolism; glyoxylate and dicarboxylate metabolism, and cysteine and methionine metabolism.
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Zakaria NF, Hamid M, Khayat ME. Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor. Nutrients 2021; 13:nu13072229. [PMID: 34209599 PMCID: PMC8308393 DOI: 10.3390/nu13072229] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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Affiliation(s)
- Nur Fatini Zakaria
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Muhajir Hamid
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Mohd Ezuan Khayat
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
- Correspondence:
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Bardanzellu F, Puddu M, Peroni DG, Fanos V. The clinical impact of maternal weight on offspring health: lights and shadows in breast milk metabolome. Expert Rev Proteomics 2021; 18:571-606. [PMID: 34107825 DOI: 10.1080/14789450.2021.1940143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Pre-pregnancy overweight and obesity, depending on maternal nutrition and metabolic state, can influence fetal, neonatal and long-term offspring health, regarding cardio-metabolic, respiratory, immunological and cognitive outcomes. Thus, maternal weight can act, through mechanisms that are not full understood, on the physiology and metabolism of some fetal organs and tissues, to adapt themselves to the intrauterine environment and nutritional reserves. These effects could occur by modulating gene expression, neonatal microbiome, and through breastfeeding. AREAS COVERED In this paper, we investigated the potential effects of metabolites found altered in breast milk (BM) of overweight/obese mothers, through an extensive review of metabolomics studies, and the potential short- and long-term clinical effects in the offspring, especially regarding overweight, glucose homeostasis, insulin resistance, oxidative stress, infections, immune processes, and neurodevelopment. EXPERT OPINION Metabolomics seems the ideal tool to investigate BM variation depending on maternal or fetal/neonatal factors. In particular, BM metabolome alterations according to maternal conditions were recently pointed out in cases of gestational diabetes, preeclampsia, intrauterine growth restriction and maternal overweight/obesity. In our opinion, even if BM is the food of choice in neonatal nutrition, the deepest comprehension of its composition in overweight/obese mothers could allow targeted supplementation, to improve offspring health and metabolic homeostasis.
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Affiliation(s)
- Flaminia Bardanzellu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari. SS 554 km 4,500, 09042 Monserrato. Italy
| | - Melania Puddu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari. SS 554 km 4,500, 09042 Monserrato. Italy
| | - Diego Giampietro Peroni
- Clinical and Experimental Medicine Department, section of Pediatrics, University of Pisa, Italy. Via Roma, 55, 56126 Pisa PI, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari. SS 554 km 4,500, 09042 Monserrato. Italy
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Jhanji M, Rao CN, Sajish M. Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation. GeroScience 2021; 43:1171-1200. [PMID: 33244652 PMCID: PMC7690980 DOI: 10.1007/s11357-020-00295-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD+-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.
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Affiliation(s)
- Megha Jhanji
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Chintada Nageswara Rao
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Mathew Sajish
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
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Sun YV, Liu C, Staimez L, Ali MK, Chang H, Kondal D, Patel S, Jones D, Mohan V, Tandon N, Prabhakaran D, Quyyumi AA, Narayan KMV, Agrawal A. Cardiovascular disease risk and pathophysiology in South Asians: can longitudinal multi-omics shed light? Wellcome Open Res 2021; 5:255. [PMID: 34136649 PMCID: PMC8176264 DOI: 10.12688/wellcomeopenres.16336.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in South Asia, with rapidly increasing prevalence of hypertension, type 2 diabetes (T2DM) and hyperlipidemia over the last two decades. Atherosclerotic CVD (ASCVD) affects South Asians earlier in life and at lower body weights, which is not fully explained by differential burden of conventional risk factors. Heart failure (HF) is a complex clinical syndrome of heterogeneous structural phenotypes including two major clinical subtypes, HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). The prevalence of HF in South Asians is also rising with other metabolic diseases, and HFpEF develops at younger age and leaner body mass index in South Asians than in Whites. Recent genome-wide association studies, epigenome-wide association studies and metabolomic studies of ASCVD and HF have identified genes, metabolites and pathways associated with CVD traits. However, these findings were mostly driven by samples of European ancestry, which may not accurately represent the CVD risk at the molecular level, and the unique risk profile of CVD in South Asians. Such bias, while formulating hypothesis-driven research studies, risks missing important causal or predictive factors unique to South Asians. Importantly, a longitudinal design of multi-omic markers can capture the life-course risk and natural history related to CVD, and partially disentangle putative causal relationship between risk factors, multi-omic markers and subclinical and clinical ASCVD and HF. In conclusion, combining high-resolution untargeted metabolomics with epigenomics of rigorous, longitudinal design will provide comprehensive unbiased molecular characterization of subclinical and clinical CVD among South Asians. A thorough understanding of CVD-associated metabolomic profiles, together with advances in epigenomics and genomics, will lead to more accurate estimates of CVD progression and stimulate new strategies for improving cardiovascular health.
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Affiliation(s)
- Yan V. Sun
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Chang Liu
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Lisa Staimez
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Mohammed K. Ali
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Howard Chang
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | | | - Shivani Patel
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Dean Jones
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | | | - Nikhil Tandon
- All India Institute of Medical Sciences, New Delhi, India
| | | | - Arshed A. Quyyumi
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - K. M. Venkat Narayan
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Anurag Agrawal
- Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, New Delhi, India
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Matsumoto S, Nakamura T, Nagamatsu F, Kido J, Sakamoto R, Nakamura K. Metabolic and biological changes in children with obesity and diabetes. World J Meta-Anal 2021; 9:153-163. [DOI: 10.13105/wjma.v9.i2.153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/23/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
The World Health Organization has stated that obesity in childhood is one of the most serious public health challenges of the 21st century. Overweightness and obesity in early childhood lead to a higher risk of overweightness and obesity in adulthood, thus conferring an increased risk of chronic inflammatory conditions, including type 2 diabetes mellitus, cardiovascular diseases, non-alcoholic fatty liver disease, and some cancers. Therefore, metabolome analysis, targeted at screening and intervening in childhood obesity, is very important. Recent studies have indicated that amino acid and lipid metabolism could influence metabolic pathways in children with obesity. For this review, we searched clinical data addressing metabolomic profiles and insulin resistance (IR) in children with obesity from inception to February 2021 in Medline, Web of Science, and Scopus. According to our search, branched-chain amino acids (BCAAs), aromatic amino acids, and acylcarnitines have reportedly been associated with IR as biomarkers for diabetes in children. BCAAs, tyrosine, and phenylalanine could be predictors of the future development of diabetes in nondiabetic subjects. In addition, it is well known that insulin regulates BCAA metabolism, and BCAA is a biomarker for IR. To interpret the mechanism behind metabolic changes in obesity, it is very important to understand the pathways and combinations related with amino acid, lipid and glucose metabolism. In this review, we summarize studies on metabolic changes to understand metabolomics in children with obesity.
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Affiliation(s)
- Shirou Matsumoto
- Department of Pediatrics, Faculty of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Tomomi Nakamura
- Department of Perinatal Care Unit, Kumamoto University Hospital, Kumamoto University, Kumamoto 860-8556, Japan
| | - Fusa Nagamatsu
- Department of Pediatrics, Faculty of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Jun Kido
- Department of Pediatrics, Faculty of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Rieko Sakamoto
- Department of Perinatal Care Unit, Kumamoto University Hospital, Kumamoto University, Kumamoto 860-8556, Japan
| | - Kimotoshi Nakamura
- Department of Pediatrics, Faculty of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Castro A, Duft RG, Silva LM, Ferreira MLV, Andrade ALL, Bernardes CF, Cavaglieri CR, Chacon-Mikahil MPT. Understanding the Relationship between Intrinsic Cardiorespiratory Fitness and Serum and Skeletal Muscle Metabolomics Profile. J Proteome Res 2021; 20:2397-2409. [PMID: 33909435 PMCID: PMC8280739 DOI: 10.1021/acs.jproteome.0c00905] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intrinsic cardiorespiratory fitness (iCRF) indicates the CRF level in the sedentary state. However, even among sedentary individuals, a wide interindividual variability is observed in the iCRF levels, whose associated molecular characteristics are little understood. This study aimed to investigate whether serum and skeletal muscle metabolomics profiles are associated with iCRF, measured by maximal power output (MPO). Seventy sedentary young adults were submitted to venous blood sampling, a biopsy of the vastus lateralis muscle and iCRF assessment. Blood serum and muscle tissue samples were analyzed by proton nuclear magnetic resonance (1H NMR) spectroscopy. Metabolites related to iCRF were those supported by three levels of evidence: (1) correlation with iCRF, (2) significant difference between individuals with low and high iCRF, and (3) metabolite contribution to significant pathways associated with iCRF. From 43 serum and 70 skeletal muscle analyzed metabolites, iCRF was positively associated with levels of betaine, threonine, proline, ornithine, and glutamine in serum and lactate, fumarate, NADP+, and formate in skeletal muscle. Serum betaine and ornithine and skeletal muscle lactate metabolites explained 31.2 and 16.8%, respectively, of the iCRF variability in addition to body mass. The results suggest that iCRF in young adults is positively associated with serum and skeletal muscle metabolic levels, indicative of the amino acid and carbohydrate metabolism.
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Affiliation(s)
- Alex Castro
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - Renata G Duft
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - Lucas M Silva
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - Marina L V Ferreira
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - André L L Andrade
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil.,School of Medical Sciences, University of Campinas, Campinas 13083-887, São Paulo, Brazil
| | - Celene F Bernardes
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - Cláudia R Cavaglieri
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
| | - Mara P T Chacon-Mikahil
- Laboratory of Exercise Physiology, School of Physical Education, University of Campinas, Campinas 13083-851, São Paulo, Brazil
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Matsumoto S, Nakamura T, Nagamatsu F, Kido J, Sakamoto R, Nakamura K. Metabolic and biological changes in children with obesity and diabetes. World J Meta-Anal 2021. [DOI: 10.13105/wjma.v9.i2.152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Jachthuber Trub C, Balikcioglu M, Freemark M, Bain J, Muehlbauer M, Ilkayeva O, White PJ, Armstrong S, Østbye T, Grambow S, Gumus Balikcioglu P. Impact of lifestyle Intervention on branched-chain amino acid catabolism and insulin sensitivity in adolescents with obesity. ENDOCRINOLOGY DIABETES & METABOLISM 2021; 4:e00250. [PMID: 34277974 PMCID: PMC8279626 DOI: 10.1002/edm2.250] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Revised: 02/16/2021] [Accepted: 03/13/2021] [Indexed: 12/30/2022]
Abstract
Insulin resistance in adolescents with obesity associates with a sex‐dependent metabolic ‘signature’ comprising branched‐chain amino acids (BCAAs), glutamate and C3/C5 acylcarnitines (C3/C5), implicating altered flux through BCAA catabolic pathways. Here, we investigated the effects of lifestyle intervention on BCAA catabolism and insulin sensitivity. We hypothesized (1) weight reduction and improved insulin sensitivity associate with enhanced BCAA catabolism; (2) baseline BCAAs and their metabolic by‐products predict changes in weight and insulin sensitivity during lifestyle intervention.
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Affiliation(s)
| | | | - Michael Freemark
- Division of Pediatric Endocrinology and Diabetes and the Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
| | - James Bain
- Duke Molecular Physiology Institute Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
| | - Michael Muehlbauer
- Duke Molecular Physiology Institute Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
| | - Olga Ilkayeva
- Duke Molecular Physiology Institute Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
| | - Phillip J White
- Duke Molecular Physiology Institute Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
| | - Sarah Armstrong
- Division of General Pediatrics Duke University Medical Center Durham NC USA.,Department of Family Medicine and Community Health Duke University Medical Center Durham NC USA.,Department of Population Health Sciences Duke University Medical Center Durham NC USA.,Duke Clinical Research Institute Duke University Medical Center Durham NC USA
| | - Truls Østbye
- Department of Family Medicine and Community Health Duke University Medical Center Durham NC USA
| | - Steven Grambow
- Department of Biostatistics and Bioinformatics Duke University Medical Center Durham NC USA
| | - Pinar Gumus Balikcioglu
- Division of Pediatric Endocrinology and Diabetes and the Duke Molecular Physiology Institute Duke University Medical Center Durham NC USA
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Rasooli SA, Fathi R, Golzar FAK, Baghersalimi M. The effect of circuit resistance training on plasma levels of amino acids, alpha-hydroxybutyrate, mannose, and urinary levels of glycine conjugated adducts in obese adolescent boys. Appl Physiol Nutr Metab 2020; 46:561-570. [PMID: 33151749 DOI: 10.1139/apnm-2020-0171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Few studies have examined the improving effects of exercise on the association between metabolites of impaired protein metabolism and insulin resistance in obese children. Therefore, this study aims to investigate the effect of circuit resistance training (CRT) on plasma levels of amino acids, alpha-hydroxybutyrate (α-HB), mannose, and urinary levels of glycine conjugated adducts in obese adolescent boys. Forty obese adolescent boys (body mass index above the 95th percentile) with an age range of 14-17 years were randomly divided into the CRT group (n = 20) and control group (n = 20). The CRT program (3 times/week, 70%-80% of 1-repetition maximum) was performed for 8 weeks. The results indicated that the body composition and plasma levels of glucose, insulin resistance, valine, mannose, lysine, and the sum of branched-chain amino acids (BCAA) were decreased because of CRT. The plasma levels of asparagine, glycine, serine, and urinary levels of glycine conjugated adduct also increased in the CRT group. Although α-HB level decreased during CRT, it had no significant difference from that of the control group. It can be concluded that the improvement in obesity complications including insulin resistance in obese adolescent boys after CRT may be due to decrease in plasma levels of mannose and BCAA and increase urinary metabolites. Novelty: CRT improves glucose metabolism and insulin resistance in obese adolescent boys. CRT decreases plasma levels of mannose and BCAA and normalizes other amino acids. CRT increases urinary levels of glycine conjugated adducts.
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Affiliation(s)
- Seyed Ali Rasooli
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran.,Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Rozita Fathi
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran.,Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Farhad Ahmadi-Kani Golzar
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran.,Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Masoumeh Baghersalimi
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran.,Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
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Insulin Resistance in Obese Children: What Can Metabolomics and Adipokine Modelling Contribute? Nutrients 2020; 12:nu12113310. [PMID: 33137934 PMCID: PMC7692749 DOI: 10.3390/nu12113310] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
The evolution of obesity and its resulting comorbidities differs depending upon the age of the subject. The dramatic rise in childhood obesity has resulted in specific needs in defining obesity-associated entities with this disease. Indeed, even the definition of obesity differs for pediatric patients from that employed in adults. Regardless of age, one of the earliest metabolic complications observed in obesity involves perturbations in glucose metabolism that can eventually lead to type 2 diabetes. In children, the incidence of type 2 diabetes is infrequent compared to that observed in adults, even with the same degree of obesity. In contrast, insulin resistance is reported to be frequently observed in children and adolescents with obesity. As this condition can be prerequisite to further metabolic complications, identification of biological markers as predictive risk factors would be of tremendous clinical utility. Analysis of obesity-induced modifications of the adipokine profile has been one classic approach in the identification of biomarkers. Recent studies emphasize the utility of metabolomics in the analysis of metabolic characteristics in children with obesity with or without insulin resistance. These studies have been performed with targeted or untargeted approaches, employing different methodologies. This review summarizes some of the advances in this field while emphasizing the importance of the different techniques employed.
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Sun YV, Liu C, Staimez L, Ali MK, Chang H, Kondal D, Patel S, Jones D, Mohan V, Tandon N, Prabhakaran D, Quyyumi AA, Narayan KMV, Agrawal A. Cardiovascular disease risk and pathophysiology in South Asians: can longitudinal multi-omics shed light? Wellcome Open Res 2020; 5:255. [PMID: 34136649 PMCID: PMC8176264 DOI: 10.12688/wellcomeopenres.16336.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2020] [Indexed: 03/27/2025] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in South Asia, with rapidly increasing prevalence of hypertension, type 2 diabetes and hyperlipidemia over the last two decades. Atherosclerotic CVD (ASCVD) affects South Asians earlier in life and at lower body weights, which is not fully explained by differential burden of conventional risk factors. Heart failure (HF) is a complex clinical syndrome of heterogeneous structural phenotypes including two major clinical subtypes, HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). The prevalence of HF in South Asians is also rising with other metabolic diseases, and HFpEF develops at younger age and leaner body mass index in South Asians than in Whites. Recent genome-wide association studies, epigenome-wide association studies and metabolomic studies of ASCVD and HF have identified genes, metabolites and pathways associated with CVD traits. However, these findings were mostly driven by samples of European ancestry, which may not accurately represent the CVD risk at the molecular level, and the unique risk profile of CVD in South Asians. Such bias, while formulating hypothesis-driven research studies, risks missing important causal or predictive factors unique to South Asians. Importantly, a longitudinal design of multi-omic markers can capture the life-course risk and natural history related to CVD, and partially disentangle putative causal relationship between risk factors, multi-omic markers and subclinical and clinical ASCVD and HF. In conclusion, combining high-resolution untargeted metabolomics with epigenomics of rigorous, longitudinal design will provide comprehensive unbiased molecular characterization of subclinical and clinical CVD among South Asians. A thorough understanding of CVD-associated metabolomic profiles, together with advances in epigenomics and genomics, will lead to more accurate estimates of CVD progression and stimulate new strategies for improving cardiovascular health.
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Affiliation(s)
- Yan V. Sun
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Chang Liu
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Lisa Staimez
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Mohammed K. Ali
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
- Department of Family and Preventive Medicine, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Howard Chang
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | | | - Shivani Patel
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Dean Jones
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | | | - Nikhil Tandon
- All India Institute of Medical Sciences, New Delhi, India
| | | | - Arshed A. Quyyumi
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - K. M. Venkat Narayan
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Anurag Agrawal
- Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, New Delhi, India
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Li R, Huang X, Liang X, Su M, Lai KP, Chen J. Integrated omics analysis reveals the alteration of gut microbe-metabolites in obese adults. Brief Bioinform 2020; 22:5882185. [PMID: 32770198 DOI: 10.1093/bib/bbaa165] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity, a risk to health, is a global problem in modern society. The prevalence of obesity was approximately 13% among world's adult population. Recently, several reports suggested that the interference of gut microbiota composition and function is associated with metabolic disorders, including obesity. Gut microbiota produce a board range of metabolites involved in energy and glucose homeostasis, leading to the alteration in host metabolism. However, systematic evaluation of the relationship between gut microbiota, gut metabolite and host metabolite profiles in obese adults is still lacking. In this study, we used comparative metagenomics and metabolomics analysis to determine the gut microbiota and gut-host metabolite profiles in six normal and obese adults of Chinese origin, respectively. Following the functional and pathway analysis, we aimed to understand the possible impact of gut microbiota on the host metabolites via the change in gut metabolites. The result showed that the change in gut microbiota may result in the modulation of gut metabolites contributing to glycolysis, tricarboxylic acid cycle and homolactic fermentation. Furthermore, integrated metabolomic analysis demonstrated a possible positive correlation of dysregulated metabolites in the gut and host, including l-phenylalanine, l-tyrosine, uric acid, kynurenic acid, cholesterol sulfate and glucosamine, which were reported to contribute to metabolic disorders such as obesity and diabetes. The findings of this study provide the possible association between gut microbiota-metabolites and host metabolism in obese adults. The identified metabolite changes could serve as biomarkers for the evaluation of obesity and metabolic disorders.
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Affiliation(s)
| | | | | | - Min Su
- Guilin Medical University
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Bardanzellu F, Puddu M, Peroni DG, Fanos V. The Human Breast Milk Metabolome in Overweight and Obese Mothers. Front Immunol 2020; 11:1533. [PMID: 32793208 PMCID: PMC7385070 DOI: 10.3389/fimmu.2020.01533] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 06/10/2020] [Indexed: 12/15/2022] Open
Abstract
Pre-pregnancy body mass index (BMI) is a major relevance factor, since maternal overweight and obesity can impair the pregnancy outcome and represent risk factors for several neonatal, childhood, and adult conditions, including excessive weight gain, cardiovascular disease, diabetes mellitus, and even behavioral disorders. Currently, breast milk (BM) composition in such category of mothers was not completely defined. In this field, metabolomics represents the ideal technology, able to detect the whole profile of low molecular weight molecules in BM. Limited information is available on human BM metabolites differences in overweight or obese compared to lean mothers. Analyzing all the metabolomics studies published on Medline in English language, this review evaluated the effects that 8 specific types of metabolites found altered by maternal overweight and obesity (nucleotide derivatives, 5-methylthioadenosine, sugar-alcohols, acylcarnitine and amino acids, polyamines, mono-and oligosaccharides, lipids) can exert on the risk of offspring obesity development and other potentially associated health outcomes and complications. However, metabolites variations in samples collected from overweight and obese mothers and the potentially correlated effects highlighted below still need further investigations and should be confirmed in future metabolomics studies on larger samples. Finally, the positive or negative influence of maternal overweight and obesity on the offspring, potentially exerted by breastfeeding, should be analyzed in close correlation with maternal age, genetic and environmental factors, including diet, and taking into account the interactions occurring between BM metabolites and lactobiome. The evaluation of all the factors affecting BM metabolites in overweight and obese mothers can lead to the comprehensive description of such biofluid and the related effects on breastfed subjects, potentially highlighting personalized needs of BM supplementation or short- and long-term prevention strategies to optimize offspring health.
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Affiliation(s)
- Flaminia Bardanzellu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari, Monserrato, Italy
| | - Melania Puddu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari, Monserrato, Italy
| | - Diego Giampietro Peroni
- Clinical and Experimental Medicine Department, Section of Pediatrics, University of Pisa, Pisa, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU and University of Cagliari, Monserrato, Italy
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Palomino-Schätzlein M, Mayneris-Perxachs J, Caballano-Infantes E, Rodríguez MA, Palomo-Buitrago ME, Xiao X, Mares R, Ricart W, Simó R, Herance JR, Fernández-Real JM. Combining metabolic profiling of plasma and faeces as a fingerprint of insulin resistance in obesity. Clin Nutr 2020; 39:2292-2300. [DOI: 10.1016/j.clnu.2019.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/17/2019] [Accepted: 10/19/2019] [Indexed: 12/13/2022]
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Hosking J, Pinkney J, Jeffery A, Cominetti O, Da Silva L, Collino S, Kussmann M, Hager J, Martin FP. Insulin Resistance during normal child growth and development is associated with a distinct blood metabolic phenotype (Earlybird 72). Pediatr Diabetes 2019; 20:832-841. [PMID: 31254470 DOI: 10.1111/pedi.12884] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/22/2019] [Accepted: 06/19/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND While insulin resistance (IR) is associated with specific metabolite signatures in adults, there have been few truly longitudinal studies in healthy children, either to confirm which abnormalities are present, or to determine whether they precede or result from IR. Therefore, we investigated the association of serum metabolites with IR in childhood in the Earlybird cohort. METHODS The Earlybird cohort is a well-characterized cohort of healthy children with annual measurements from age 5 to 16 years. For the first time, longitudinal association analyses between individual serum metabolites and homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR) have been performed taking into account the effects of age, growth, puberty, adiposity, and physical activity. RESULTS IR was higher in girls than in boys and was associated with increasing body mass index (BMI). In longitudinal analysis IR was associated with reduced concentrations of branched-chain amino acids (BCAA), 2-ketobutyrate, citrate and 3-hydroxybutyrate, and higher concentrations of lactate and alanine. These findings demonstrate the widespread biochemical consequences of IR for intermediary metabolism, ketogenesis, and pyruvate oxidation during normal child growth and development. CONCLUSIONS Longitudinal analysis can differentiate metabolite signatures that precede or follow the development of greater levels of IR. In healthy normal weight children, higher levels of IR are associated with reduced levels of BCAA, ketogenesis, and fuel oxidation. In contrast, elevated lactate concentrations preceded the rise in IR. These changes reveal the metabolite signature of insulin action during normal growth, and they contrast with previous findings in obese children and adults that represent the consequences of IR and obesity.
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Affiliation(s)
- Joanne Hosking
- Faculty of Medicine and Dentistry, Plymouth University, Plymouth, UK
| | - Jonathan Pinkney
- Faculty of Medicine and Dentistry, Plymouth University, Plymouth, UK
| | - Alison Jeffery
- Faculty of Medicine and Dentistry, Plymouth University, Plymouth, UK
| | - Ornella Cominetti
- Department of Analytical Sciences, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
| | - Laeticia Da Silva
- Department of Analytical Sciences, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
| | - Sebastiano Collino
- Department of Analytical Sciences, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
| | - Martin Kussmann
- Department of Analytical Sciences, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
| | - Jorg Hager
- Department of Nutrition and Dietary recommendations, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
| | - Francois-Pierre Martin
- Department of Metabolic Health, Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland
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Abstract
Metabolomics uses advanced analytical chemistry techniques to enable the high-throughput characterization of metabolites from cells, organs, tissues, or biofluids. The rapid growth in metabolomics is leading to a renewed interest in metabolism and the role that small molecule metabolites play in many biological processes. As a result, traditional views of metabolites as being simply the "bricks and mortar" of cells or just the fuel for cellular energetics are being upended. Indeed, metabolites appear to have much more varied and far more important roles as signaling molecules, immune modulators, endogenous toxins, and environmental sensors. This review explores how metabolomics is yielding important new insights into a number of important biological and physiological processes. In particular, a major focus is on illustrating how metabolomics and discoveries made through metabolomics are improving our understanding of both normal physiology and the pathophysiology of many diseases. These discoveries are yielding new insights into how metabolites influence organ function, immune function, nutrient sensing, and gut physiology. Collectively, this work is leading to a much more unified and system-wide perspective of biology wherein metabolites, proteins, and genes are understood to interact synergistically to modify the actions and functions of organelles, organs, and organisms.
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Affiliation(s)
- David S Wishart
- Departments of Biological Sciences and Computing Science, University of Alberta, Edmonton, Alberta, Canada
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47
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Short KR, Chadwick JQ, Teague AM, Tullier MA, Wolbert L, Coleman C, Copeland KC. Effect of Obesity and Exercise Training on Plasma Amino Acids and Amino Metabolites in American Indian Adolescents. J Clin Endocrinol Metab 2019; 104:3249-3261. [PMID: 31216576 PMCID: PMC6584131 DOI: 10.1210/jc.2018-02698] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/05/2019] [Indexed: 12/12/2022]
Abstract
CONTEXT Amino acids (AAs) and their metabolites are altered with obesity and may be predictive of future diabetes in adults, but there are fewer studies on AAs, as well as conflicting findings on how they vary with obesity, in adolescents. OBJECTIVE To determine whether plasma AAs vary with body composition and insulin sensitivity and are altered in response to exercise training. DESIGN Cross-sectional, and an exercise intervention. SETTING Tribal wellness center. PARTICIPANTS American Indian boys and girls, 11 to 17 years of age with obesity (Ob, n = 58) or normal weight (NW, n = 36). INTERVENTION The Ob group completed 16 weeks of aerobic exercise training. MAIN OUTCOME MEASURE A panel of 42 plasma AAs. RESULTS Compared with the NW group, the Ob group had lower aerobic fitness and insulin sensitivity (interactive homeostasis model assessment 2), 17 AAs that were higher, and 7 AAs that were lower. Branched-chain AAs (+10% to 16%), aromatic AAs (+15% to 32%), and glutamate were among the higher AAs; all were positively correlated with body fat and negatively correlated with insulin sensitivity. The lysine metabolite 2-aminoadipic acid (2-AAA) and the valine metabolite β-aminoisobutyric acid (BAIBA) were 47% higher and 29% lower, respectively, in the Ob group, and were positively (2-AAA) and negatively (BAIBA) correlated with insulin sensitivity. Exercise training increased aerobic fitness by 10%, but body composition, insulin sensitivity, and AAs were not significantly changed. CONCLUSIONS Several plasma AAs are altered in American Indian adolescents with obesity and are associated with insulin sensitivity, but they were not altered with this exercise intervention.
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Affiliation(s)
- Kevin R Short
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Correspondence and Reprint Requests: Kevin R. Short, PhD, 1200 Children’s Avenue, Suite 4500, Oklahoma City, Oklahoma 73104. E-mail:
| | - Jennifer Q Chadwick
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - April M Teague
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | | | | | | | - Kenneth C Copeland
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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48
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Rangel-Huerta OD, Pastor-Villaescusa B, Gil A. Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies. Metabolomics 2019; 15:93. [PMID: 31197497 PMCID: PMC6565659 DOI: 10.1007/s11306-019-1553-y] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 06/01/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Obesity is a disorder characterized by a disproportionate increase in body weight in relation to height, mainly due to the accumulation of fat, and is considered a pandemic of the present century by many international health institutions. It is associated with several non-communicable chronic diseases, namely, metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cancer. Metabolomics is a useful tool to evaluate changes in metabolites due to being overweight and obesity at the body fluid and cellular levels and to ascertain metabolic changes in metabolically unhealthy overweight and obese individuals (MUHO) compared to metabolically healthy individuals (MHO). OBJECTIVES We aimed to conduct a systematic review (SR) of human studies focused on identifying metabolomic signatures in obese individuals and obesity-related metabolic alterations, such as inflammation or oxidative stress. METHODS We reviewed the literature to identify studies investigating the metabolomics profile of human obesity and that were published up to May 7th, 2019 in SCOPUS and PubMed through an SR. The quality of reporting was evaluated using an adapted of QUADOMICS. RESULTS Thirty-three articles were included and classified according to four types of approaches. (i) studying the metabolic signature of obesity, (ii) studying the differential responses of obese and non-obese subjects to dietary challenges (iii) studies that used metabolomics to predict weight loss and aimed to assess the effects of weight loss interventions on the metabolomics profiles of overweight or obese human subjects (iv) articles that studied the effects of specific dietary patterns or dietary compounds on obesity-related metabolic alterations in humans. CONCLUSION The present SR provides state-of-the-art information about the use of metabolomics as an approach to understanding the dynamics of metabolic processes involved in human obesity and emphasizes metabolic signatures related to obesity phenotypes.
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Affiliation(s)
- Oscar Daniel Rangel-Huerta
- Faculty of Medicine, Department of Nutrition, University of Oslo, Oslo, Norway
- Norwegian Veterinary Institute, Oslo, Norway
| | - Belén Pastor-Villaescusa
- LMU - Ludwig-Maximilians-Universität München, Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich Medical Center, Munich, Germany
- Institute of Epidemiology, Helmholtz Zentrum München-German Research Centre for Environmental Health, Neuherberg, Germany
| | - Angel Gil
- Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology "José Mataix, Centre for Biomedical Research, University of Granada", Granada, Spain.
- Instituto de Investigación Biosanitaria ibs-Granada, Granada, Spain.
- Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBEROBN), Madrid, Spain.
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NMR-Based Metabolomic Approach Tracks Potential Serum Biomarkers of Disease Progression in Patients with Type 2 Diabetes Mellitus. J Clin Med 2019; 8:jcm8050720. [PMID: 31117294 PMCID: PMC6571571 DOI: 10.3390/jcm8050720] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/10/2019] [Accepted: 05/15/2019] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia associated with alterations in carbohydrate, lipid, and protein metabolism. The prognosis of T2DM patients is highly dependent on the development of complications, and therefore the identification of biomarkers of T2DM progression, with minimally invasive techniques, is a huge need. In the present study, we applied a 1H-Nuclear Magnetic Resonance (1H-NMR)-based metabolomic approach coupled with multivariate data analysis to identify serum metabolite profiles associated with T2DM development and progression. To perform this, we compared the serum metabolome of non-diabetic subjects, treatment-naïve non-complicated T2DM patients, and T2DM patients with complications in insulin monotherapy. Our analysis revealed a significant reduction of alanine, glutamine, glutamate, leucine, lysine, methionine, tyrosine, and phenylalanine in T2DM patients with respect to non-diabetic subjects. Moreover, isoleucine, leucine, lysine, tyrosine, and valine levels distinguished complicated patients from patients without complications. Overall, the metabolic pathway analysis suggested that branched-chain amino acid (BCAA) metabolism is significantly compromised in T2DM patients with complications, while perturbation in the metabolism of gluconeogenic amino acids other than BCAAs characterizes both early and advanced T2DM stages. In conclusion, we identified a metabolic serum signature associated with T2DM stages. These data could be integrated with clinical characteristics to build a composite T2DM/complications risk score to be validated in a prospective cohort.
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Cree-Green M, Carreau AM, Rahat H, Garcia-Reyes Y, Bergman BC, Pyle L, Nadeau KJ. Amino acid and fatty acid metabolomic profile during fasting and hyperinsulinemia in girls with polycystic ovarian syndrome. Am J Physiol Endocrinol Metab 2019; 316:E707-E718. [PMID: 30753112 PMCID: PMC6580169 DOI: 10.1152/ajpendo.00532.2018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Polycystic ovarian syndrome (PCOS) is associated with insulin resistance (IR) and altered muscle mitochondrial oxidative phosphorylation. IR in adults with obesity and diabetes is associated with changes in amino acid, free fatty acid (FFA), and mitochondrial acylcarnitine (AC) metabolism. We sought to determine whether these metabolites are associated with IR and/or androgens in youth-onset PCOS. We enrolled obese girls with PCOS [ n = 15, 14.5 yr (SD 1.6), %BMI 98.5 (SD 1.0)] and without PCOS [ n = 6, 13.2 yr (SD 1.2), %BMI 98.0 (SD 1.1)]. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. Untargeted metabolomics of plasma was performed while fasting and during hyperinsulinemia. Fasting arginine, glutamine, histidine, lysine, phenylalanine, and tyrosine were higher ( P < 0.04 for all but P < 0.001 for valine), as were glutamine and histidine during hyperinsulinemia ( P < 0.03). Higher valine during hyperinsulinemia was associated with IR ( r = 0.59, P = 0.006). Surprisingly, end-clamp AC C4 was lower in PCOS, and lower C4 was associated with IR ( r = -0.44, P = 0.04). End-clamp FFAs of C14:0, C16:1, and C18:1 were higher in PCOS girls, and C16:1 and C18:1 strongly associated with IR ( r = 0.73 and 0.53, P < 0.01). Free androgen index related negatively to short-, medium-, and long-chain AC ( r = -0.41 to -0.71, P < 0.01) but not FFA or amino acids. Obese girls with PCOS have a distinct metabolic signature during fasting and hyperinsulinemia. As in diabetes, IR related to valine and FFAs, with an unexpected relationship with AC C4, suggesting unique metabolism in obese girls with PCOS.
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Affiliation(s)
- Melanie Cree-Green
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
- Center for Women's Health Research , Aurora, Colorado
| | - Anne-Marie Carreau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Haseeb Rahat
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Yesenia Garcia-Reyes
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Bryan C Bergman
- Department of Medicine, Division of Endocrinology and Metabolism, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Laura Pyle
- Department of Biostatistics and Informatics, Colorado School of Public Health , Aurora, Colorado
- Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Kristen J Nadeau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus , Aurora, Colorado
- Center for Women's Health Research , Aurora, Colorado
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