Abstract
High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert ‘rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality.
Highlights
The uniform shift to higher levels of insulin in mice on high fat diet (HFD) may represent ‘normal elevation’ of insulin associated with obesity and/or aging
Rapamycin slows down aging in mammals, whereas resveratrol increases insulin sensitivity in mice on HFD
We demonstrated that low-dose rapamycin and resveratrol prevented hyperinsulinemia in male mice on HFD
Summary
Low dose rapamycin does not prevent weight gain in male mice on HFD. Mice were fed either regular food or high fat (60% fat) diet (Figure 1). All the mice on HFD had higher levels of insulin than regular diet mice. While 8 out of 10 mice on HFD had Bequal levels of insulin (which were higher than levels in any mouse on regular diet), two mice had exceptionally high levels of insulin. Two exacerbated cases can be viewed as obesity-induced disease, because the levels of insulin in these two mice deviated from the ‘normal’ elevation of insulin, observed in mice on HFD. Disease can be viewed as exacerbated ‘normal’ trend associated with HFD (or with aging in other cases). Administrated separately, both resveratrol and rapamycin decreased HFD-induced hyperinsulinemia albeit the effect was not statistically significant.
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