title: Nitric Oxide Exerts Basal and Insulin-Dependent Anorexigenic Actions in POMC Hypothalamic Neurons.
abstract: The arcuate nucleus of the hypothalamus represents a key center for the control of appetite and feeding through the regulation of 2 key neuronal populations, notably agouti-related peptide/neuropeptide Y and proopimelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons. Altered regulation of these neuronal networks, in particular the dysfunction of POMC neurons upon high-fat consumption, is a major pathogenic mechanism involved in the development of obesity and type 2 diabetes mellitus. Efforts are underway to preserve the integrity or enhance the functionality of POMC neurons in order to prevent or treat these metabolic diseases. Here, we report for the first time that the nitric oxide (NO(-)) donor, sodium nitroprusside (SNP) mediates anorexigenic actions in both hypothalamic tissue and hypothalamic-derived cell models by mediating the up-regulation of POMC levels. SNP increased POMC mRNA in a dose-dependent manner and enhanced α-melanocortin-secreting hormone production and secretion in mHypoA-POMC/GFP-2 cells. SNP also enhanced insulin-driven POMC expression likely by inhibiting the deacetylase activity of sirtuin 1. Furthermore, SNP enhanced insulin-dependent POMC expression, likely by reducing the transcriptional repression of Foxo1 on the POMC gene. Prolonged SNP exposure prevented the development of insulin resistance. Taken together, the NO(-) donor SNP enhances the anorexigenic potential of POMC neurons by promoting its transcriptional expression independent and in cooperation with insulin. Thus, increasing cellular NO(-) levels represents a hormone-independent method of promoting anorexigenic output from the existing POMC neuronal populations and may be advantageous in the fight against these prevalent disorders.
authors.affiliation: Department of Physiology (L.W., J.A.C., D.D.B.), University of Toronto, Toronto, Ontario, Canada M5G 1A8; and Departments of Obstetrics, Gynaecology, and Medicine (D.D.B.), University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Leigh
authors.initials: L
authors.lastname: Wellhauser
authors.affiliation: Department of Physiology (L.W., J.A.C., D.D.B.), University of Toronto, Toronto, Ontario, Canada M5G 1A8; and Departments of Obstetrics, Gynaecology, and Medicine (D.D.B.), University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chalmers
authors.affiliation: Department of Physiology (L.W., J.A.C., D.D.B.), University of Toronto, Toronto, Ontario, Canada M5G 1A8; and Departments of Obstetrics, Gynaecology, and Medicine (D.D.B.), University of Toronto and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D001067:Appetite Depressants; D007328:Insulin; D009599:Nitroprusside; D009569:Nitric Oxide; D011333:Pro-Opiomelanocortin