Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice

Abstract

Obesity and adiposity greatly increase 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 and insulin resistance. In order to determine the effect of SCD1 deficiency on various mouse models of obesity, we introduced a global deletion of the Scd1 gene into leptin-deficient ob/ob mice, leptin-resistant Agouti (A(y)/a) mice, and high-fat diet-fed obese (DIO) mice. SCD1 deficiency lowered body weight, adiposity, hepatic lipid accumulation, and hepatic lipogenic gene expression in all three mouse models. However, glucose tolerance, insulin, and leptin sensitivity were improved by SCD1 deficiency only in A(y)/a and DIO mice, but not ob/ob mice. These data uncouple the effects of SCD1 deficiency on weight loss from those on insulin sensitivity and suggest a beneficial effect of SCD1 inhibition on insulin sensitivity in obese mice that express a functional leptin gene.

Fig. 1. Body weight, food intake, and adiposity

A. Food intake was measured at 16 weeks of age. B–D. Body weight was measured up to 16 weeks in ob/ob mice (B) and up to 20 weeks in A^y/a (C) and DIO (D) mice. High-fat feeding in DIO mice was started at 8 weeks of age. E. All animals were sacrificed at 24 weeks of age. Gonadal white adipose mass was measured. F. Fresh liver sections were fixed with 10% buffered formalin and stained by hematoxylin and eosin to visualize lipid droplets. Sections are representative of several animals in each group. G, H. Hepatic (G) and plasma (H) triglycerides were measured in 24 week-old mice. I. Expression of hepatic lipogenic genes was measured by real-time PCR using gene-specific primers. The relative quantification for a given gene was corrected to the ribosomal protein L32 mRNA values. Data represent the mean + SE for >4 animals in each group. p<0.05 compared to ^# Scd1^+/+ chow and ^**compared to respective Scd1^+/+ counterparts.

Fig 2. Oral glucose tolerance and insulin signaling

A. Oral glucose tolerance was assessed in fasted animals by measuring plasma glucose at 0 and 90 minutes post-gavage of 10% glucose at a dose of 2 g/kg body weight. B. Fasting plasma insulin levels were measured by RIA. C. Components of the insulin signaling pathway were measured in liver and red gastrocnemius. IR, insulin receptor. ^**compared to respective Scd1^+/+ counterparts.

Fig. 3. Plasma leptin and leptin sensitivity

A. 24 week-old males were fasted for 4 hours and sacrificed with isoflurane overdose. Plasma leptin levels were measured by ELISA. B-E. 12 week-old males were subcutaneously infused with leptin at a rate of 0.2 μg/day/g body weight. Data is presented as percent change from basal body weight and food intake. Change in body weight was measured in leptin-infused A^y/a (B) and DIO (C) mice. Change in food intake was measured in leptin-infused A^y/a (D) and DIO mice (E). Data represent the mean + SE for >4 animals in each group. p<0.05 compared to ^#Scd1^+/+ chow and ^**compared to respective Scd1^+/+ counterparts.