SCD1 deficiency decreases hepatic lipogenesis and improves insulin sensitivity in obese mice in the presence of leptin

Abstract

Obesity greatly increases the risk for secondary conditions such as insulin resistance. Mice deficient in the enzyme stearoyl CoA desaturase‐1 (SCD1) are lean and protected from diet‐induced obesity as well as insulin resistance, despite marked hyperphagia. In order to determine if SCD1 deficiency ameliorates obesity‐induced insulin resistance, we introduced the SCD1 mutation into three mouse models of obesity:1) leptin‐deficient ob/ob, 2) leptin‐resistant Agouti (Ay/a) and 3) high‐fat diet‐induced obese (DIO) mice. SCD1 deficiency resulted in significantly lower body weight and adiposity in all three mouse models. Hepatic lipid accumulation and lipogenic gene expression were dramatically reduced by SCD1 deficiency in all mouse models of obesity. While these changes in body mass and composition translated to increased glucose tolerance and insulin sensitivity in Ay/a and DIO mice, SCD1−/−;ob/ob mice remained hyperglycemic and hyperinsulinemic, despite significantly decreased body weight, adiposity and hepatic lipid accumulation. Upon subcutaneous leptin infusion, SCD1 deficiency potentiated weight loss in both Ay/a and DIO mice without any changes in food intake. These results uncouple the effects of SCD1 deficiency on weight loss from those on insulin sensitivity and point to increased peripheral leptin sensitivity as a potential mechanism for increased insulin signaling in SCD1−/− mice.