Metabotypes of response to bariatric surgery independent of the magnitude of weight loss

Objective Bariatric surgery is considered the most efficient treatment for morbid obesity and its related diseases. However, its role as a metabolic modifier is not well understood. We aimed to determine biosignatures of response to bariatric surgery and elucidate short-term metabolic adaptations. Methods We used a LC- and FIA-ESI-MS/MS approach to quantify acylcarnitines, (lyso)phosphatidylcholines, sphingomyelins, amino acids, biogenic amines and hexoses in serum samples of subjects with morbid obesity (n = 39) before and 1, 3 and 6 months after bariatric surgery. K-means cluster analysis allowed to distinguish metabotypes of response to bariatric surgery. Results For the first time, global metabolic changes following bariatric surgery independent of the baseline health status of the subjects have been revealed. We identify two metabolic phenotypes (metabotypes) at the interval 6 months-baseline after surgery, which presented differences in the levels of compounds of urea metabolism, gluconeogenic precursors and (lyso)phospholipid particles. Clinically, metabotypes were different in terms of the degree of improvement in insulin resistance, cholesterol, low-density lipoproteins and uric acid independent of the magnitude of weight loss. Conclusions This study opens new perspectives and new hypotheses on the metabolic benefits of bariatric surgery and understanding of the biology of obesity and its associated diseases.

[1]  O. Fiehn,et al.  Chemical Similarity Enrichment Analysis (ChemRICH) as alternative to biochemical pathway mapping for metabolomic datasets , 2017, Scientific Reports.

[2]  Huijue Jia,et al.  Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention , 2017, Nature Medicine.

[3]  Jidong Cheng,et al.  Metformin ameliorates high uric acid-induced insulin resistance in skeletal muscle cells , 2017, Molecular and Cellular Endocrinology.

[4]  F. Tinahones,et al.  Biomarkers of Morbid Obesity and Prediabetes by Metabolomic Profiling of Human Discordant Phenotypes. , 2016, Clinica chimica acta; international journal of clinical chemistry.

[5]  F. Tinahones,et al.  Metabolomics‐guided insights on bariatric surgery versus behavioral interventions for weight loss , 2016, Obesity.

[6]  W. Lieb,et al.  Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies , 2016, PloS one.

[7]  Hong Wang,et al.  Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation , 2016, Arteriosclerosis, thrombosis, and vascular biology.

[8]  F. Rubino,et al.  Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations , 2016, Diabetes Care.

[9]  M. Lanaspa,et al.  Uric acid in metabolic syndrome: From an innocent bystander to a central player. , 2016, European journal of internal medicine.

[10]  M. Levy,et al.  Essential phospholipids prevent islet damage induced by proinflammatory cytokines and hypoxic conditions , 2016, Diabetes/metabolism research and reviews.

[11]  L. Beilin,et al.  Lipidomics Reveals Associations of Phospholipids With Obesity and Insulin Resistance in Young Adults. , 2016, The Journal of clinical endocrinology and metabolism.

[12]  Y. Bao,et al.  Metabolomics Study of Roux-en-Y Gastric Bypass Surgery (RYGB) to Treat Type 2 Diabetes Patients Based on Ultraperformance Liquid Chromatography-Mass Spectrometry. , 2016, Journal of proteome research.

[13]  H. González-Pacheco,et al.  HDL-sphingomyelin reduction after weight loss by an energy-restricted diet is associated with the improvement of lipid profile, blood pressure, and decrease of insulin resistance in overweight/obese patients. , 2016, Clinica chimica acta; international journal of clinical chemistry.

[14]  L. Tenori,et al.  Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner. , 2015, The American journal of clinical nutrition.

[15]  F. Rubino,et al.  Bariatric–metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial , 2015, The Lancet.

[16]  F. Tinahones,et al.  New and vintage solutions to enhance the plasma metabolome coverage by LC-ESI-MS untargeted metabolomics: the not-so-simple process of method performance evaluation. , 2015, Analytical chemistry.

[17]  A. Xu,et al.  Lower Fetuin-A, Retinol Binding Protein 4 and Several Metabolites after Gastric Bypass Compared to Sleeve Gastrectomy in Patients with Type 2 Diabetes , 2014, PloS one.

[18]  E. Gibney,et al.  Relationship between the lipidome, inflammatory markers and insulin resistance. , 2014, Molecular bioSystems.

[19]  M. Lanaspa,et al.  Uric acid‐dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  C. Argmann,et al.  Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. , 2013, Human molecular genetics.

[21]  Jianjin Guo,et al.  Hyperuricemia Causes Pancreatic β-Cell Death and Dysfunction through NF-κB Signaling Pathway , 2013, PloS one.

[22]  M. Aslan,et al.  Early Postoperative Changes of HDL Subfraction Profile and HDL-Associated Enzymes After Laparoscopic Sleeve Gastrectomy , 2013, Obesity Surgery.

[23]  F. Tinahones,et al.  Postprandial hypertriglyceridemia predicts improvement in insulin resistance in obese patients after bariatric surgery. , 2013, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[24]  H. Abdi,et al.  Multiple factor analysis: principal component analysis for multitable and multiblock data sets , 2013 .

[25]  A. Peters,et al.  Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach , 2013, Diabetes.

[26]  C. Gieger,et al.  Human serum metabolic profiles are age dependent , 2012, Aging cell.

[27]  Ara W. Darzi,et al.  Metabolic phenotyping in clinical and surgical environments , 2012, Nature.

[28]  M. Lanaspa,et al.  Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress , 2012, The Journal of Biological Chemistry.

[29]  F. Tinahones,et al.  Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy. , 2012, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[30]  Peter Kovacs,et al.  Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes. , 2011, Journal of proteome research.

[31]  Svati H Shah,et al.  Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss , 2011, Science Translational Medicine.

[32]  Bernard Thorens,et al.  Uric acid transport and disease. , 2010, The Journal of clinical investigation.

[33]  K. Clément,et al.  Metabolite Profiling Identifies Candidate Markers Reflecting the Clinical Adaptations Associated with Roux-en-Y Gastric Bypass Surgery , 2009, PloS one.

[34]  C. Hoppel,et al.  Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. , 2009, The Journal of nutrition.

[35]  M. Jensen,et al.  Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. , 2009, The American journal of medicine.

[36]  Pengxiang She,et al.  Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. , 2007, American journal of physiology. Endocrinology and metabolism.

[37]  Marko Sysi-Aho,et al.  Acquired Obesity Is Associated with Changes in the Serum Lipidomic Profile Independent of Genetic Effects – A Monozygotic Twin Study , 2007, PloS one.

[38]  P. Shah,et al.  Active oxygen species and lysophosphatidylcholine are involved in oxidized low density lipoprotein activation of smooth muscle cell DNA synthesis. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[39]  H. Akaike.  A new look at the statistical model identification , 1974 .

[40]  J. Griffin,et al.  Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. , 2014, The lancet. Diabetes & endocrinology.

[41]  J. Mckenney,et al.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). , 2001, JAMA.

[42]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .