High-fat diet-induced obesity and insulin resistance were ameliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice.

摘要

Tumor necrosis factor-alpha (TNF-alpha) is one of the main mediators of inflammatory response activated by fatty acids in obesity, and this signaling through TNF-alpha receptor (TNFR) is responsible for obesity-associated insulin resistance. Recently, TNF-alpha has shown to affect lipid metabolism including the regulation of lipase activity and bile acid synthesis. However, there is scanty in vivo evidence for the involvement of TNF-alpha in this process, and the mechanistic role of TNFR remains unclear. In this study, TNFR2 knockout mice (R2KO) and wild-type (WT) mice were fed commercial normal diet (ND) or high-fat diet (HFD) for 8 weeks. In R2KO/HFD mice, the increase in body weight and the accumulation of fat were significantly ameliorated compared with WT/HFD mice in association with the decrease in plasma total cholesterol (137.7+/-3.1 vs. 98.6+/-3.1 mg/dL, P<0.005), glucose (221.9+/-14.7 vs. 167.3+/-8.1 mg/dL, P<0.01), and insulin (5.1+/-0.3 vs. 3.4+/-0.3 ng/mL, P<0.05). Fecal excretion of lipid contents was significantly increased in R2KO mice. In R2KO/HFD mice, the decrease in hepatic cholesterol-7a-hydroxylase activity, the rate-limiting enzyme in bile acid synthesis, was inhibited (1.7+/-0.2 vs. 8.1+/-1.0 pmol/min/mg protein, P<0.01). These results suggested that HFD-induced obesity with metabolic derangements could be ameliorated in mice lacking TNF-alpha receptor 2 via increasing fecal bile acid and lipid content excretion. Therefore, TNF-alpha signaling through TNFR2 is essentially involved in the bile acid synthesis and excretion of lipids, resulting in its beneficial effects.