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

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)636-646
Number of pages11
JournalCell Reports
Volume18
Issue number3
DOIs
Publication statusPublished - 17 Jan 2017
Externally publishedYes

Keywords

  • Journal Article
  • Research Support, Non-U.S. Gov't

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