Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin’s orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.
Sun Y, Wang P, Zheng H, Smith RG (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci U S A 101: 4679–4684.
Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649–661.
Seoane LM, López M, Tovar S, Casanueva F, Se？arís R, et al. (2003) Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology 144: 544–551.
Lage R, Vázquez MJ, Varela L, Saha AK, Vidal-Puig A, et al. (2010) Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J 24: 2670–2679.
Nogueiras R, López M, Lage R, Pérez-Tilve D, Pfluger P, et al. (2008) Bsx, a Novel Hypothalamic Factor linking Feeding with Locomotor Activity, is Regulated by Energy Availability. Endocrinology 149: 3009–3015.
Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, et al. (2010) Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes 59: 2426–2434.
Ropelle ER, Pauli JR, Fernandes MF, Rocco SA, Marin RM, et al. (2008) A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes 57: 594–605.
Reed AS, Unger EK, Olofsson LE, Piper ML, Myers MG Jr, et al. (2010) Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59: 894–906.
López M, Seoane LM, García MC, Diéguez C, Se？arís R (2002) Neuropeptide Y, but not agouti-related peptide or melanin-concentrating hormone, is a target Peptide for orexin-a feeding actions in the rat hypothalamus. Neuroendocrinology 75: 34–44.
López M, Lelliott CJ, Tovar S, Kimber W, Gallego R, et al. (2006) Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 55: 1327–1336.
Roa J, García-Galiano D, Varela L, Sánchez-Garrido MA, Pineda R, et al. (2009) The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150: 5016–5026.
Villanueva EC, Munzberg H, Cota D, Leshan RL, Kopp K, et al. (2009) Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 150: 4541–4551.