Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance
Maxwell A. Ruby,
Julie Massart,
Devon M. Hunerdosse,
Milena Schönke,
Jorge C. Correia,
Sharon M. Louie,
Jorge L. Ruas,
Erik Näslund,
Daniel K. Nomura,
Juleen R. Zierath
Affiliations
Maxwell A. Ruby
Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Julie Massart
Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Devon M. Hunerdosse
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
Milena Schönke
Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Jorge C. Correia
Molecular and Cellular Exercise Physiology Unit, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
Sharon M. Louie
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
Jorge L. Ruas
Molecular and Cellular Exercise Physiology Unit, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
Erik Näslund
Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 17177 Stockholm, Sweden
Daniel K. Nomura
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
Juleen R. Zierath
Section for Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
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.
