title: Inactivation of Socs3 in the hypothalamus enhances the hindbrain response to endogenous satiety signals via oxytocin signaling.
abstract: Leptin is an adipocyte-derived hormone that controls energy balance by acting primarily in the CNS, but its action is lost in common forms of obesity due to central leptin resistance. One potential mechanism for such leptin resistance is an increased hypothalamic expression of Suppressor of cytokine signaling 3 (Socs3), a feedback inhibitor of the Jak-Stat pathway that prevents Stat3 activation. Ample studies have confirmed the important role of Socs3 in leptin resistance and obesity. However, the degree to which Socs3 participates in the regulation of energy homeostasis in nonobese conditions remains largely undetermined. In this study, using adult mice maintained under standard diet, we demonstrate that Socs3 deficiency in the mediobasal hypothalamus (MBH) reduces food intake, protects against body weight gain, and limits adiposity, suggesting that Socs3 is necessary for normal body weight maintenance. Mechanistically, MBH Socs3-deficient mice display increased hindbrain sensitivity to endogenous, meal-related satiety signals, mediated by oxytocin signaling. Thus, oxytocin signaling likely mediates the effect of hypothalamic leptin on satiety circuits of the caudal brainstem. This provides an anatomical substrate for the effect of leptin on meal size, and more generally, a mechanism for how the brain controls short-term food intake as a function of the energetic stores available in the organism to maintain energy homeostasis. Any dysfunction in this pathway could potentially lead to overeating and obesity.
authors.affiliation: Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille UMR 7286, 13344 Marseille cedex 15, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Matarazzo
authors.forename: Fabienne
authors.initials: F
authors.lastname: Schaller
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nédélec
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benani
authors.forename: Luc
authors.initials: L
authors.lastname: Pénicaud
authors.forename: Françoise
authors.initials: F
authors.lastname: Muscatelli
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moyse
authors.forename: Sylvian
authors.initials: S
authors.lastname: Bauer
mesh_terms: D000818:Animals; D020109:Devazepide / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D010121:Oxytocin / Q000378:metabolism*; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism*; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D020738:Leptin; D011949:Receptors, Cholecystokinin; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D010121:Oxytocin; D020109:Devazepide