The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity.
Journal of Neuroscience. 2008-07-09; 28(28): 7202-7208
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1. J Neurosci. 2008 Jul 9;28(28):7202-8. doi: 10.1523/JNEUROSCI.1389-08.2008.
The role of hypothalamic mammalian target of rapamycin complex 1 signaling in
Cota D(1), Matter EK, Woods SC, Seeley RJ.
(1)Department of Psychiatry, University of Cincinnati, Genome Research Institute,
Cincinnati, Ohio 45237, USA.
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.
PMID: 18614690 [Indexed for MEDLINE]