Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance

Ruby, Maxwell A., Massart, Julie, Hunerdosse, Devon M., Schönke, Milena, Correia, Jorge C., Louie, Sharon M., Ruas, Jorge L., Näslund, Erik, Nomura, Daniel K. and Zierath, Juleen R. (2017) Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance. Cell Reports, 18 (3). pp. 636-646. ISSN 2211-1247

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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.

Item Type: Article
Additional Information: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Uncontrolled Keywords: journal article,research support, non-u.s. gov't,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Depositing User: Pure Connector
Date Deposited: 15 Dec 2017 06:07
Last Modified: 31 Aug 2023 09:30
DOI: 10.1016/j.celrep.2016.12.070

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