Hypothalamic mTOR Research Articles

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 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.

Role of Leucine in Regulating Food Intake

In their recent Report “Hypothalamic mTOR signaling regulates food intake” (12 May, p. [927][1]), D. Cota et al. detail the metabolic mechanisms controlling food intake and show that increased hypothalamic availability of the branched-chain amino acid (BCAA) leucine acts as a potent signal that

A Cellular Fuel Sensor

The brain plays a key role in body weight control. Within the hypothalamus, select populations of neurons sense changes in fuel availability and regulate food intake and metabolism, but the underlying signaling mechanisms have not been well understood. Cota et al. (see the Perspective by Flier) implicate the atypical kinase mTOR (mammalian target of rapamycin) signaling pathway, which has been widely studied in other cell types, where it regulates the rate of protein synthesis. In rodents, central administration of leucine, which increases mTOR signaling in nonneuronal cells, activated hypothalamic mTOR signaling and decreased food intake and body weight. D. Cota, K. Proulx, K. A. Blake Smith, S. C. Kozma, G. Thomas, S. C. Woods, R. J. Seeley, Hypothalamic mTOR signaling regulates food intake. Science 312 , 927-930 (2006). [Abstract] [Full Text] J. S. Flier, Regulating energy balance: The substrate strikes back. Science 312 , 861-864 (2006). [Summary] [Full Text]

Hypothalamic mTOR Signaling Regulates Food Intake

The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.