Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat.

Abstract

What is the central question of this study? Whether chronic oral rapamycin promotes beneficial effects on glucose/lipid metabolism and energy balance when administered to mice with an obesogenic diet rich in saturated fat and sucrose has not been explored. What is the main finding and its importance? Chronic oral rapamycin reduces body weight and fat gain, improves insulin sensitivity and reduces hepatic steatosis when administered to mice with a high-fat, high-sucrose diet. In addition, we make the new observation that there appear to be tissue-specific effects of rapamycin. Although rapamycin appears to impart its effects mainly on visceral adipose tissue, its effects on insulin sensitivity are mediated by subcutaneous adipose tissue. Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient-sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity-associated insulin resistance. Given that increased tissue activation of mTOR complex-1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet-induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high-fat, high-sucrose (HFHS) diet for 20weeks. The control group received placebo microcapsules. Rapamycin-treated mice showed significantly reduced weight gain and adiposity (33.6±4.9versus 40.4±3.0% body fat, P<0.001, n=8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin-fed mice also demonstrated reduced plasma glucose (252±57versus 297±67mgdl-1 , P<0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin-treated mice also had lower plasma triglycerides (48±13 versus 67±11 mg/dL, P<0.01) and hepatic triglyceride content (89±15versus 110±19 mg/g liver, P<0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity. These data suggest that low-grade chronic mTORC1 inhibition might be a potential strategy for anti-obesity therapies.