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

The mammalian target of rapamycin (mTOR) kinase is a key regulator of several cellular functions, including cell growth and differentiation. Because hypothalamic mTOR complex 1 (mTORC1) signaling has been implicated as a target of leptin in the regulation of energy balance, we investigated its role in obesity-induced leptin resistance. In contrast to rats maintained on a low-fat (LF) diet for 3 weeks, rats maintained on a high-fat (HF)-diet had no anorexic response to intracerebroventricular leptin. Western blot analysis revealed that leptin was unable to modulate hypothalamic mTORC1 signaling in the HF group, whereas it significantly induced phosphorylation of both S6 kinase 1 (S6K1) and S6 ribosomal protein (S6) in the LF group. Similar to leptin, the cytokine ciliary neurotrophic factor (CNTF) induces hypophagia and increases signal transduction activator of transcription 3 phosphorylation. However, CNTF and its analog CNTFAx15 activate leptin-like pathways in the hypothalamus, even in leptin-resistant states, including diet-induced obesity. Intracerebroventricular CNTFAx15 decreased 24 h food intake and body weight in rats on HF or LF diets and increased the phosphorylation of hypothalamic S6K1 and S6 in a comparable way in both diets. Importantly, mice lacking the expression of S6K1 (S6K1−/−) did not respond to the anorectic action of either leptin or CNTFAx15, implying a crucial role for S6K1 in modulating the actions of these two cytokines. Finally, exposure to HF diet decreased mTORC1 signaling within the hypothalamus. Overall, these findings point strongly to the possibility that reduced hypothalamic mTORC1 signaling contributes to the development of hyperphagia, weight gain, and leptin resistance during diet-induced obesity.

[1]  Yoshiji Yamada,et al.  Genetic factors for human obesity , 2008, Cellular and Molecular Life Sciences.

[2]  A. Sahu,et al.  Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. , 2008, Endocrinology.

[3]  M. M. Dias,et al.  A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss , 2008, Diabetes.

[4]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[5]  B. Kahn,et al.  Diet-induced Obesity Alters AMP Kinase Activity in Hypothalamus and Skeletal Muscle* , 2006, Journal of Biological Chemistry.

[6]  Yi Zhang,et al.  The role of leptin in leptin resistance and obesity , 2006, Physiology & Behavior.

[7]  George Thomas,et al.  Hypothalamic mTOR Signaling Regulates Food Intake , 2006, Science.

[8]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[9]  A. Pocai,et al.  Central leptin acutely reverses diet-induced hepatic insulin resistance. , 2005, Diabetes.

[10]  H. Münzberg,et al.  Molecular and anatomical determinants of central leptin resistance , 2005, Nature Neuroscience.

[11]  S. Woods,et al.  Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[12]  A. Marette,et al.  Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. , 2005, Endocrinology.

[13]  S. Woods,et al.  Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. , 2004, The Journal of clinical investigation.

[14]  C. Mantzoros,et al.  Ciliary neurotrophic factorAx15 alters energy homeostasis, decreases body weight, and improves metabolic control in diet-induced obese and UCP1-DTA mice. , 2004, Diabetes.

[15]  H. Münzberg,et al.  Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. , 2004, Endocrinology.

[16]  S. Woods,et al.  Monitoring of stored and available fuel by the CNS: implications for obesity , 2003, Nature Reviews Neuroscience.

[17]  S. Woods,et al.  A controlled high-fat diet induces an obese syndrome in rats. , 2003, The Journal of nutrition.

[18]  Alexander S. Banks,et al.  STAT3 signalling is required for leptin regulation of energy balance but not reproduction , 2003, Nature.

[19]  James O. Hill,et al.  Obesity and the Environment: Where Do We Go from Here? , 2003, Science.

[20]  E. Air,et al.  Insulin and leptin combine additively to reduce food intake and body weight in rats. , 2002, Endocrinology.

[21]  G. Yancopoulos,et al.  Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Flier,et al.  Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. , 2000, The Journal of clinical investigation.

[23]  Stefano Fumagalli,et al.  Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase , 1998, The EMBO journal.

[24]  B. Popkin.  Understanding global nutrition dynamics as a step towards controlling cancer incidence , 2007, Nature Reviews Cancer.

[25]  C. Mantzoros,et al.  Ciliary Neurotrophic FactorAx 15 Alters Energy Homeostasis , Decreases Body Weight , and Improves Metabolic Control in Diet-Induced Obese and UCP 1-DTA Mice , 2004 .