Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive accumulation of triacylglycerol in peripheral tissues is tightly associated with obesity and has been identified as an independent risk factor for insulin resistance, type 2 diabetes, and cardiovascular complications. Here we show that ablation of carboxylesterase 3 (Ces3)/triacylglycerol hydrolase (TGH) expression in mice (Tgh(-/-)) results in decreased plasma triacylglycerol, apolipoprotein B, and fatty acid levels in both fasted and fed states. Despite the attenuation of very low-density lipoprotein secretion, TGH deficiency does not increase hepatic triacylglycerol levels. Tgh(-/-) mice exhibit increased food intake, respiratory quotient, and energy expenditure without change in body weight. These metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance. Tgh(-/-) mice have smaller sized pancreatic islets but maintain normal glucose-stimulated insulin secretion. These studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels.
 ...
PMID:Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. 2019 51

Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.
...
PMID:Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes. 2448 3

The role of carboxylesterase 3 (Ces3) in the lipolysis of adipocytes has been overlooked, as 2 major lipolytic enzymes, hormone-sensitive lipase and adipose triglyceride lipase, play more powerful roles in lipolysis. In this study, we explored the effects of Ces3 in lipid metabolism by activating and inhibiting, as well as silencing, Ces3-encoding gene in 3T3-L1 cell model. Our results demonstrated that activation of Ces3 increased adipogenesis, and attenuated lipogenesis, whereas it promoted lipolysis and fatty acid oxidation. In addition, activated Ces3 led to enhanced expression of core fat browning marker genes and proteins, suggesting that Ces3 may play a pivotal role in fat browning and thermogenesis. In contrast, deficiency of Ces3 nullified the browning effect in white adipocytes, along with decreased adipogenesis in 3T3-L1 adipocytes. Interestingly, the expression pattern of adipose triglyceride lipase was in line with Ces3, whereas hormone-sensitive lipase was independently regulated irrespective of Ces3 expression levels, suggesting that Ces3 may play an important and compensatory role in the breakdown of triglycerides in white adipocytes. In conclusion, we provide the first evidence that activation of Ces3 contributes in the browning of white adipocytes, and maintains a balance in lipid metabolism, which could be a potential strategy in fighting against obesity.
 ...
PMID:Novel regulatory roles of carboxylesterase 3 in lipid metabolism and browning in 3T3-L1 white adipocytes. 3080 12