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Complex Regulation of Mammalian Target of Rapamycin Complex 1 in the Basomedial Hypothalamus by Leptin and Nutritional Status

Division of Metabolism, Endocrinology, and Diabetes (E.C.V., H.M., R.L.L., K.K., R.I.-T., J.C.J., D.C.F., M.G.M.), Department of Internal Medicine, and Departments of Molecular and Integrative Physiology (E.C.V., R.L.L., M.G.M.) and Cell and Developmental Biology (D.C.F.), University of Michigan, Ann Arbor, Michigan 48109; Department of Psychiatry (D.C., R.J.S.), Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237; and Institut National de la Santé et de la Recherche Médicale Unité 862 (D.C.), NuroCentre Magendie, 33077 Bordeaux, France

Address all correspondence and requests for reprints to: Martin G. Myers, Jr., M.D., Ph.D., Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, University of Michigan, 5560 MSRB II/0678, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109. E-mail: mgmyers{at}umich.edu.; or Heike Muenzberg, Ph.D., Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: heike.munzberg{at}pbrc.edu.

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.