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

Abstract

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT1-deficient mice are resistant to diet-induced obesity through a mechanism involving increased energy expenditure. Here we show that these mice have decreased levels of tissue triglycerides, as well as increased sensitivity to insulin and to leptin. Importantly, DGAT1 deficiency protects against insulin resistance and obesity in agouti yellow mice, a model of severe leptin resistance. In contrast, DGAT1 deficiency did not affect energy and glucose metabolism in leptin-deficient (ob/ob) mice, possibly due in part to a compensatory upregulation of DGAT2 expression in the absence of leptin. Our results suggest that inhibition of DGAT1 may be useful in treating insulin resistance and leptin resistance in human obesity.

Figure 1

Decreased adipocyte size in Dgat1^–/– mice. Each circle represents the mean adipocyte surface area of one female mouse. More than 100 adipocytes were measured per mouse. For high-fat experiments, mice were fed a high-fat diet for 10 weeks.

Figure 2

Increased insulin sensitivity in Dgat1^–/– mice. (a) Glucose tolerance test. (b) Insulin tolerance test. (c) Hyperinsulinemic-euglycemic clamp study. n = 5–6 chow-fed male mice per genotype in each experiment. *P < 0.05 versus Dgat1^+/+ mice.

Figure 3

Increased weight loss in response to leptin infusion in Dgat1^–/– mice. (a and b) Body weight. (c and d) Food intake. Sex-, age-, and weight-matched mice were used. n = 6–8 chow-fed mice per genotype. Error bars represent SEM. **P < 0.01 versus Dgat1^+/+ mice receiving the same dose of leptin.

Figure 4

Expression of leptin-regulated genes in Dgat1^–/– mice. The expression of UCP1 was examined in BAT. The expression of other genes was examined in WAT. For PPARα and leptin, results were obtained with real-time PCR. For other genes, results were obtained with Northern blotting. n = 4–6 chow-fed male mice per genotype. *P < 0.05 versus Dgat1^+/+ mice.

Figure 5

Effects of DGAT1 deficiency on energy and glucose metabolism in Agouti yellow (A^Y/a) and leptin-deficient (ob/ob) mice. n = 8–12 mice per genotype for growth curves, n = 5 chow-fed male mice per genotype for fat pad content, and n = 4–6 chow-fed male mice per genotype for plasma glucose and insulin concentrations. *P < 0.05, **P < 0.01 versus Dgat1^+/+ mice.

Figure 6

Increased DGAT2 mRNA expression in WAT of leptin-deficient Dgat1^–/– mice. Results were obtained with real-time PCR. n = 4–6 male mice per genotype. *P < 0.05 versus ob/ob Dgat1^+/+ mice.