Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1

Abstract

Recent studies have identified the white adipose tissue (WAT) as an important endocrine organ that regulates energy and glucose metabolism via a number of secreted factors. Mice lacking acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in mammalian triglyceride synthesis, are protected against diet-induced obesity and glucose intolerance because of increased energy expenditure and enhanced insulin sensitivity. Because DGAT1 is highly expressed in WAT, we hypothesized that DGAT1 deficiency affects the expression of adipocyte-derived factors that regulate energy and glucose metabolism. Here we show that the transplantation of DGAT1-deficient WAT decreases adiposity and enhances glucose disposal in wild-type mice. Analysis of DGAT1-deficient WAT revealed a twofold increase in the expression of adiponectin, a molecule that enhances fatty acid oxidation and insulin sensitivity, and this increase may account in part for the transplantation-induced metabolic changes. Our results highlight the importance of the endocrine function of WAT and suggest that an alteration in this function contributes to the increased energy expenditure and insulin sensitivity in DGAT1-deficient mice.

Figure 1

Histology of transplanted Dgat1^+/+ and Dgat1^–/– WAT. Representative results are shown. Bar, 100 μm.

Figure 2

Effects of WAT transplantation on body weight and total fat pad content. (a) Decreased weight gain in WAT^Dgat1–/–→Dgat1^+/+ mice fed a high-fat diet. n = 8–9 male mice per group. (b) Decreased total fat pad content (excluding transplanted fat pads) in WAT^Dgat1–/–→Dgat1^+/+ mice. n = 4–6 male mice per group. (c) Lack of effect of transplanted Dgat1^+/+ WAT on obesity resistance of Dgat1^–/– mice. n = 3–4 female mice per group. (d) Lack of effect of transplanted Dgat1^+/+ WAT on total fat pad content in Dgat1^–/– mice. n = 4 male mice per group. *P < 0.05.

Figure 3

Effects of transplanted Dgat1^–/– WAT on adiposity in mice fed a high-fat diet. (a) Decreased serum leptin levels in WAT^Dgat1–/–→Dgat1^+/+ mice. n = 4–5 male mice per group. (b) Decreased body triglyceride content in WAT^Dgat1–/–→Dgat1^+/+ mice. n = 4 male mice per group. (c) Decreased muscle triglyceride content in WAT^Dgat1–/–→Dgat1^+/+ mice. n = 3 male mice per group. (d) Similar body-protein contents in WAT^Dgat1–/–→Dgat1^+/+ and WAT^Dgat1+/+→Dgat1^+/+ mice. n = 4 male mice per group. Mice were fed a high-fat diet for 2, 5, or 12 weeks. *P < 0.05.

Figure 4

Effects of transplanted Dgat1^–/– WAT on energy intake and expenditure in mice fed a high-fat diet. (a) Energy intake and expenditure in WAT^Dgat1–/–→Dgat1^+/+ and WAT^Dgat1+/+→Dgat1^+/+ mice. n = 3–4 male mice per group. Error bars represent SEM. *P < 0.05. (b) Relationship between energy expenditure and lean body mass in WAT^Dgat1–/–→Dgat1^+/+ and WAT^Dgat1+/+→Dgat1^+/+ mice. Regression lines for both groups are shown.

Figure 5

Effects of WAT transplantation on glucose metabolism. (a and b) Enhanced glucose disposal in WAT^Dgat1–/–→Dgat1^+/+ mice. n = 5–6 chow-fed male mice per group. (c and d) Lack of effect of transplanted Dgat1^+/+ WAT on glucose disposal in Dgat1^–/– mice. n = 4 chow-fed male mice per group. *P < 0.05.

Figure 6

Metabolic effects of transplanted Dgat1^–/– WAT in A^Y/a and ob/ob mice. (a and b) Enhanced glucose disposal in WAT^{AY/aDgat1–/–}→A^Y/a Dgat1^+/+ mice. n = 4–5 chow-fed male mice per group. (c and d) Lack of effect of transplanted ob/ob Dgat1^–/– WAT on glucose disposal in ob/ob Dgat1^+/+ mice. n = 4 chow-fed male mice per group. *P < 0.05.

Figure 7

Expression of adipocyte-derived molecules. (a) Resistin, TNF-α, and adiponectin expression in WAT of Dgat1^–/– mice. n = 7–10 male mice per group. Error bars represent SEM. *P < 0.05 vs. Dgat1^+/+ mice fed a high-fat diet for 20 weeks. (b) Comparison of adiponectin expression in transplanted A^Y/a Dgat1^–/– WAT and native A^Y/a Dgat1^+/+ WAT obtained from transplanted mice. n = 4 male mice per group. *P <0.05 vs. naive WAT. (c) Effect of leptin infusion on adiponectin expression in ob/ob Dgat1^–/– mice. n = 3–5 male mice per group. Expression of chow-fed Dgat1^+/+ mice = 1.0. *P < 0.05 vs. ob/ob Dgat1^+/+ mice without leptin treatment. (d) Effect of leptin infusion on adiponectin expression in Dgat1^–/– and Dgat1^+/+ mice. n = 8–10 male mice per group.

Figure 8

Concentrations of adipocyte-derived factors in growth media conditioned by A^Y/a Dgat1^–/– or A^Y/a Dgat1^+/+ WAT. (a) Total protein. (b) FFAs. (c) Leptin. (d) TNF-α. (e) Adiponectin. n = 6–10 mice per group. *P < 0.05, **P < 0.01.

Figure 9

Increased serum adiponectin levels in WAT^Dgat1–/–→Dgat1^+/+ mice fed a high-fat diet. (a) After 2 or 5 weeks of high-fat feeding. n = 4–5 male mice per group. *P < 0.05. (b) After 20 weeks of high-fat feeding. Each lane represents a serum sample from an individual mouse. The experiment was performed twice, and representative results are shown.

Figure 10

Serum adiponectin and TNF-α levels in Dgat1^–/– mice. (a) Serum adiponectin levels in Dgat1^+/+, Dgat1^+/–, and Dgat1^–/– mice fed a high-fat diet. n = 5–7 male mice per group. P < 0.01 for all comparisons for adjusted serum concentrations. (b) Adjusted serum adiponectin levels in A^Y/a Dgat1^+/+ and A^Y/a Dgat1^–/– mice fed a chow diet. n = 5–6 male mice per group. *P < 0.01. (c) Serum TNF-α levels in Dgat1^–/– mice fed a high-fat diet. n = 5–7 male mice per group. *P < 0.05 vs. Dgat1^+/+ mice.