title: The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons.
abstract: Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several signaling proteins, including Akt, as well as the transcription of the POMC gene. These data strongly suggest that intracellular CNTF may directly modulate POMC gene expression via the activation of receptors localized in the cell nucleus, providing a novel plausible mechanism of CNTF action in regulating energy homeostasis.
authors.affiliation: Neuroendocrinologie Moléculaire de la Prise Alimentaire, University of Paris-Sud, Orsay, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Couvreur
authors.forename: Alain
authors.initials: A
authors.lastname: Aubourg
authors.forename: Delphine
authors.initials: D
authors.lastname: Crépin
authors.forename: Jéril
authors.initials: J
authors.lastname: Degrouard
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Vacher
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D008297:Male; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020934:Ciliary Neurotrophic Factor; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D011333:Pro-Opiomelanocortin