Ces1/Es-x deficiency results in obesity, impairment of glucose metabolism and decreased energy expenditure

QUIROGA, ARIEL DARIO; PARAMADAYALAN, SENTHAMIL; LI, LENA; LEHNER, RICHARD

Edmonton

Jornada; Alberta Diabetes Institute (ADI) Research Day; 2010

Obesity is a metabolic disorder characterized by chronic inflammation and dyslipidemia. Accumulation of triacylglycerol (TG) in peripheral tissues is related with obesity and it is a risk factor for insulin resistance and type-2-diabetes. The mammalian carboxylesterases (Ces) are members of the serine/esterase family. Ces proteins are localized in the endoplasmic reticulum of many tissues. These enzymes catalyze the hydrolysis of a variety of ester- and amide-containing compounds. We found that ablation of carboxylesterase 3 (Ces3)/triacylglycerol hydrolase (TGH) in mice results in decreased plasma TG and fatty acid levels, accompanied by improved insulin sensitivity and glucose tolerance. Another carboxylesterase closely related to Ces3/TGH is esterase-x (Ces1/Es-x). Mouse Ces1/Es-x shares ~76% protein sequence homology with Ces3/TGH. We hypothesized that, as Ces3/TGH, Ces1/Es-x participates in lipid metabolism affecting whole body metabolism. We generated global Ces1/Es-x-/- mice and showed that under a chow diet, Ces1/Es-x deficiency leads to increased body weight, increased adiposity, increased blood lipid levels and accumulation of lipids in the liver. Ces1/Es-x-/- mice present decreased blood glucose levels but normal glucose tolerance, accompanied by increased plasma insulin levels and decreased insulin sensitivity compared to wild-types. Ces1/Es-x-/- mice exhibit decreased respiratory quotient and energy expenditure. These studies make Ces1/Es-x a striking pharmacological candidate for preventing hepatic steatosis and obesity and therefore type-2-diabetes.