Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Abstract

SummarySerine 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.

Intestine‐Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet‐Induced Liver Steatosis and Obesity

“…Body weight and body mass composition of Ces2c int mice were comparable to controls on chow. However, on HFD, Ces2c int mice were protected from diet‐induced obesity and liver steatosis, highlighting an important function of Ces2c in the small intestine during metabolic stress, as suggested for hepatic Ces2c / CES2 . In line with the aforementioned studies exploring hepatic Ces2c function, we add additional insights into the importance of Ces2c to efficiently hydrolyze TGs and DGs, thereby generating 2‐MGs in the small intestine.…”

“…C), which are typical esterase substrates. Two studies indicated that Ces2c also harbors TGH activity; however, enzymatic activities (levels of hydrolyzed FAs per time) were not indicated. To characterize the enzymatic function of Ces2c, we measured FA release by TGH and DGH activities in cell lysates prepared from COS‐7 cells overexpressing FLAG‐tagged Ces2c as described .…”

“…Low hepatic expression of Ces2c / CES2 has been linked to NAFLD development in obese mice and humans . The aforementioned studies suggested that reduced Ces2c/CES2 expression during metabolic stress lowers hepatic TG catabolism at the endoplasmic reticulum (ER), thereby decreasing hepatic FAO but stimulating ER stress–induced lipogenesis.…”

“…The search for alternative TGHs in murine CGI‐58‐deficient tissues through activity‐based protein profiling revealed a marked increase in Ces2c protein expression (unpublished). Recently, two independent studies demonstrated that Ces2c/CES2 can act as a TGH and that reduced hepatic expression of Ces2c/CES2 is linked to NAFLD development in obese mice and humans . Ces2c is expressed in lipoprotein‐producing organs with highest expression levels in the duodenum .…”

Kudingcha and Fuzhuan Brick Tea Prevent Obesity and Modulate Gut Microbiota in High‐Fat Diet Fed Mice

“…Obesity has become a major public health problem worldwide, and its prevalence has dramatically increased over several decades . Furthermore, it is associated with other diseases such as nonalcoholic fatty liver, type 2 diabetes, hypertension, coronary artery disease, and various forms of cancer . A growing body of evidence has shown that gut microbiota plays a critical role in nutrient acquisition, energy harvest, and lipid metabolism, which may contribute to the metabolic diseases .…”