title: Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.
abstract: Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.
authors.affiliation: Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Maxwell A
authors.initials: MA
authors.lastname: Ruby
authors.affiliation: Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Massart
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Devon M
authors.initials: DM
authors.lastname: Hunerdosse
authors.affiliation: Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Milena
authors.initials: M
authors.lastname: Schönke
authors.affiliation: Molecular and Cellular Exercise Physiology Unit, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Correia
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Louie
authors.affiliation: Molecular and Cellular Exercise Physiology Unit, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: juleen.zierath@ki.se.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D000818:Animals; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004075:Diglycerides / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D058570:TOR Serine-Threonine Kinases; C569302:AADAC protein, human; D002265:Carboxylic Ester Hydrolases; C517204:CES2 protein, human; D043182:Carboxylesterase; D005947:Glucose
keywords: activity-based protein profiling; carboxylesterase; diacylglycerol; hepatic steatosis; inflammation; insulin resistance; lipidomics; obesity; serine hydrolase