Intestinal epithelial cell-specific Raptor is essential for high fat diet-induced weight gain in mice

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of cell growth and proliferation through fuel sensing. Systemic inhibition of mTOR as well as manipulation of its downstream products prevent diet-induced obesity. The purpose of this study was to determine the consequences of intestine-targeted mTORC1 inhibition. To attenuate intestinal mTORC1 activity, Villin-CreER mice were crossed with Raptorflox/flox mice, creating an intestinal-specific Raptor null line (i-Raptor −/−). Mice were fed a high fat diet (HFD) and compositional changes as well as food intake levels were assessed. Over a five-week time course, i-Raptor −/− mice consistently gained less body weight on a HFD compared to wildtype (WT) mice secondary to significantly reduced food intake. Importantly, the i-Raptor −/− mice did not appear to be malnourished, demonstrated by their preservation of lean body mass. i-Raptor −/− mice also maintained a normal metabolic profile without significant changes in triglyceride or fasting glucose levels. Further investigation revealed that GDF-15 mRNA expression was significantly enhanced in i-Raptor −/− enterocytes when refed with HFD after overnight starvation. In summary, our study establishes that loss of intestinal specific-mTORC1 is protective of the development of diet-induced obesity by reducing food intake without altering the metabolic profile.

Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS

“…Calorie intake impacts the gene associated with cg26633077, RPTOR , as shown in the stabilization of the MTOR-RPTOR association by nutrient deprivation, leading to inhibition of MTOR activity [ 56 ]. Despite the inhibition of the anabolic regulator MTOR, one study found that RPTOR null mice gained less weight, most likely due to reduced food intake in a high-fat diet, when compared to wild type mice [ 57 ]. It is worth noting that there was very high heterogeneity observed for cg26633077.…”