Increased insulin and leptin sensitivity in mice lacking acyl CoA : diacylglycerol acyltransferase 1 Hubert

Because obesity results from an imbalance between energy input and output, with most of the excess calories stored as triglycerides (or triacylglycerols), inhibition of triglyceride synthesis may prevent or reverse obesity (1). One of the key enzymes in triglyceride synthesis is acyl coenzyme A:diacylglycerol acyltransferase (acyl CoA:diacylglycerol acyltransferase, or DGAT), which catalyzes the final step in mammalian triglyceride synthesis. Two DGAT enzymes (DGAT1 and DGAT2) have been identified (2, 3). DGAT1 activity is widely distributed, and its gene (Dgat1) is expressed in all tissues examined (2). To investigate the effects of disrupting triglyceride synthesis on energy and glucose metabolism, we generated DGAT1-deficient (Dgat1–/–) mice (4). Dgat1–/– mice have triglycerides in their adipose tissue and normal plasma triglyceride levels. The residual triglyceride synthesis presumably occurs through the actions of DGAT2 and perhaps additional mechanisms of triglyceride synthesis (5). Dgat1–/– mice are resistant to diet-induced obesity because of increased energy expenditure. This increase is partially mediated by a twofold increase in physical activity in Dgat1–/– mice fed a high-fat diet. These mice also tend to have enhanced glucose disposal after a glucose load on either a chow or a high-fat diet (4). How does DGAT1 deficiency affect energy and glucose metabolism? One plausible mechanism is by modulating tissue triglyceride metabolism. Increased triglyceride content in tissues such as skeletal muscle and liver correlates with insulin resistance (6–8). Moreover, increased adiposity is associated with resistance to leptin, an adipocyte-derived hormone that enhances energy expenditure and insulin sensitivity (9, 10). Because DGAT1 deficiency in mice is not associated with a compensatory increase in DGAT2 mRNA expression (3), we hypothesized that Dgat1–/– mice have reduced levels of tissue triglycerides and that these reductions are associated with increased sensitivity to insulin and to leptin. To test this hypothesis, we measured tissue triglyceride levels in Dgat1–/– mice, and we performed hyperinsulinemic-euglycemic clamp and leptin infusion studies. We also studied the effects of DGAT1 deficiency on energy and glucose metabolism in agouti yellow (AY/a) and leptindeficient (ob/ob) mice, two genetic models of obesity and insulin resistance. Our findings provide new insights into how alterations in triglyceride synthesis affect insulin and leptin sensitivity.