WWL113

Mouse carboxylesterase 3 (Ces3, also named Ces 1d) mediates triglyceride hydrolysis in white adipose tissue, liberating free fatty acids into circulation. Although important for basal lipolysis, Ces3 expression can be induced by xenobiotics. Ces3 activity is significantly elevated during adipocyte differentiation. WWL113 is a selective inhibitor of Ces3 and the structurally related Ces 1f (IC50 = ~0.1 µM) without significantly affecting several related enzymes. It significantly reduces basal lipolysis in adipocytes. More interestingly, WWL113 corrects multiple features of metabolic syndrome in obese-diabetic db/db mice, including changes in weight gain, glucose tolerance, and levels of nonesterified free fatty acids, triglycerides, total cholesterol, and fasted glucose. It has similar effects in mice with diet-induced obesity. WWL113 also inhibits the human ortholog of mouse Ces3, hCES1 (IC50 = ~50 nM), which has a similar tissue expression pattern to Ces3.