The Role of Hypothalamic Mammalian Target of Rapamycin Complex 1 Signaling in Diet-Induced Obesity

S6K1^−/− mice do not respond to the anorectic action of leptin. A, S6K1^−/− mice, although smaller, have a body composition comparable with WT mice when expressed as a percentage of body weight. Eight S6K1^−/− mice and 11 WT were used. B, C, Leptin (5 mg/kg, i.p.) does not affect either food intake (B) or body weight change (C) in S6K1^−/− mice. Four to six mice (mean ± SEM) were used for each treatment group. *p < 0.05, ***p < 0.001 versus WT/PBS condition.

During exposure to an HF diet, CNTF_Ax15 induces anorexia and increases hypothalamic mTORC1 signaling. A, B, Effect of intracerebroventricular CNTF_Ax15 (1.5 μg in 2 μl of PBS) on food intake (A) and body weight (B) of rats maintained on an HF or LF diet for 3 weeks. Six to seven rats (mean ± SEM) were used for each treatment group. C, E, Intracerebroventricular CNTF_Ax15 increases hypothalamic mTORC1 signaling on the LF and HF diets. Representative Western blots from PBS- or CNTF_Ax15-treated rats are shown. Seven brains were examined in each condition. β-Actin was used as a loading control. D, F, Quantification by image analysis of hypothalamic STAT3, S6K1, and S6 phosphorylation. Error bars indicate SEM. *p < 0.05, **p < 0.005, ***p < 0.001 versus PBS condition.

The ability of CNTF_Ax15 to reduce food intake depends on functional S6K1. A, B, CNTF_Ax15 (0.6 mg/kg, i.p.) does not affect either food intake (A) or body weight change (B) in S6K1^−/− mice. Five to seven mice (mean ± SEM) were used for each treatment group. **p < 0.005 versus WT/PBS condition.