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The Journal of Neuroscience, July 9, 2008, 28(28):7202-7208; doi:10.1523/JNEUROSCI.1389-08.2008

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Behavioral/Systems/Cognitive
The Role of Hypothalamic Mammalian Target of Rapamycin Complex 1 Signaling in Diet-Induced Obesity

Daniela Cota, Emily K. Matter, Stephen C. Woods, and Randy J. Seeley

Department of Psychiatry, University of Cincinnati, Genome Research Institute, Cincinnati, Ohio 45237

Correspondence should be addressed to Dr. Daniela Cota at her present address: Equipe Avenir "Physiopathology of Energy Balance and Obesity," INSERM U862, NeuroCentre François Magendie, 146 Rue Léo Saignat, 33077 Bordeaux Cedex, France. Email: daniela.cota{at}inserm.fr

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 CNTF_Ax15 activate leptin-like pathways in the hypothalamus, even in leptin-resistant states, including diet-induced obesity. Intracerebroventricular CNTF_Ax15 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 CNTF_Ax15, 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.

Key words: mTORC1; S6K1; hypothalamus; high-fat diet; obesity; leptin resistance

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Received April 2, 2008; revised May 12, 2008; accepted May 28, 2008.

Correspondence should be addressed to Dr. Daniela Cota at her present address: Equipe Avenir "Physiopathology of Energy Balance and Obesity," INSERM U862, NeuroCentre François Magendie, 146 Rue Léo Saignat, 33077 Bordeaux Cedex, France. Email: daniela.cota{at}inserm.fr

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