PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats

Abstract

mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPARγ activity. Herein, we tested the hypothesis that pharmacological PPARγ activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg·kg(-1)·day(-1)) in combination or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPARγ activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.

Omega‐3 fatty acids protect from diet‐induced obesity, glucose intolerance, and adipose tissue inflammation through PPARγ‐dependent and PPARγ‐independent actions

“…Although the mechanisms underlying these n ‐3 actions are undefined, the absence of significant changes on food intake in any of the studies reported herein strongly indicates that this may be due to increased energy expenditure. In this sense, previous reports have found that administration of n ‐3 EPA attenuates diet‐induced obesity by increasing energy expenditure in mice, such an effect being attributed to an increase in futile substrate cycling of fatty acid reesterification but not to nonshivering thermogenesis . Furthermore, a recent study has found that fat‐1 mice fed an HFD display elevated rates of oxygen consumption and a protection against diet‐induced obesity , although the mechanisms underlying these n ‐3 actions were not delineated.…”

Rapamycin-induced metabolic defects are reversible in both lean and obese mice

“…These data raise the possibility that metabolic defects caused by long-term rapamycin use could be mitigated transient withdrawal from the treatment, or by concurrent or alternative therapies. Festuccia et al recently showed that rosiglitazone reduces hyperglycemia, glucose intolerance and insulin resistance caused by short-term treatment of rapamycin in rats [29]. It remains to be seen whether preventing metabolic dysfunction by treatments like this will further potentiate the beneficial effects of rapamycin in cancer treatment and prevention or longevity extension.…”

Exposure of pregnant mice to triclosan impairs placental development and nutrient transport

“…Rapamycin was injected intraperitoneally (i.p.) at a dose of 3.5 mg/kg/day45. LY294002 (40 μM) was administered by intrauterine injections46.…”