Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status.
Endocrinology. 2009-10-01; 150(10): 4541-4551
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1. Endocrinology. 2009 Oct;150(10):4541-51. doi: 10.1210/en.2009-0642. Epub 2009 Jul
Complex regulation of mammalian target of rapamycin complex 1 in the basomedial
hypothalamus by leptin and nutritional status.
Villanueva EC(1), Münzberg H, Cota D, Leshan RL, Kopp K, Ishida-Takahashi R,
Jones JC, Fingar DC, Seeley RJ, Myers MG Jr.
(1)Division of Metabolism, Department of Medicine, University of Michigan, Ann
Arbor, Michigan 48109, USA.
The medial basal hypothalamus, including the arcuate nucleus (ARC) and the
ventromedial hypothalamic nucleus (VMH), integrates signals of energy status to
modulate metabolism and energy balance. Leptin and feeding regulate the mammalian
target of rapamycin complex 1 (mTORC1) in the hypothalamus, and hypothalamic
mTORC1 contributes to the control of feeding and energy balance. To determine the
mechanisms by which leptin modulates mTORC1 in specific hypothalamic neurons, we
immunohistochemically assessed the mTORC1-dependent phosphorylation of ribosomal
protein S6 (pS6). In addition to confirming the modulation of ARC mTORC1 activity
by acute leptin treatment, this analysis revealed the robust activation of
mTORC1-dependent ARC pS6 in response to fasting and leptin deficiency in leptin
receptor-expressing Agouti-related protein neurons. In contrast, fasting and
leptin deficiency suppress VMH mTORC1 signaling. The appropriate regulation of
ARC mTORC1 by mutant leptin receptor isoforms correlated with their ability to
suppress the activity of Agouti-related protein neurons, suggesting the potential
stimulation of mTORC1 by the neuronal activity. Indeed, fasting- and leptin
deficiency-induced pS6-immunoreactivity (IR) extensively colocalized with
c-Fos-IR in ARC and VMH neurons. Furthermore, ghrelin, which activates orexigenic
ARC neurons, increased ARC mTORC1 activity and induced colocalized pS6- and
c-Fos-IR. Thus, neuronal activity promotes mTORC1/pS6 in response to signals of
energy deficit. In contrast, insulin, which activates mTORC1 via the
phosphatidylinositol 3-kinase pathway, increased ARC and VMH pS6-IR in the
absence of neuronal activation. The regulation of mTORC1 in the basomedial
hypothalamus thus varies by cell and stimulus type, as opposed to responding in a
uniform manner to nutritional and hormonal perturbations.
PMID: 19628573 [Indexed for MEDLINE]