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.