Hypothalamus-specific deletion of socs3 in adult mice enhances hindbrain sensitivity to endogenous satiety signals via oxytocin signaling
Résumé
Leptin is a major contributor to long-term energy homeostasis, through an intracellular transduction pathway involving activation of Stat3 and its feedback inhibitor Socs3, which limits Stat3 activation. Previous studies have shown that Socs3 haploinsufficiency or socs3 deletion in the whole brain or in selective neuronal populations triggers an increased sensitivity to exogenous leptin, through increased Stat3 activation, and protects against diet-induced obesity in mice fed a high fat diet. Intriguingly however, no phenotype was detected when Socs3 mutant mice were maintained under standard diet, suggesting that Socs3 may only contribute to energy homeostasis in pathological conditions and not in physiological conditions. In this study, we show that deletion of socs3 in the medio-basal hypothalamus, when performed in adult mice by stereotaxic injection of an adenovirus encoding Cre recombinase, produces an attenuation of body weight gain, a decreased adiposity, and a decreased food intake in animals maintained under standard diet. The decreased food intake was associated with an increased hindbrain sensitivity to endogenous satiety signals, which was blocked by fourth ventricular injection of a selective oxytocin receptor antagonist. Thus, our study indicates that Socs3 controls energy homeostasis in physiological conditions, and that oxytocin signaling functions as a downstream effector of hypothalamic leptin to enhance hindbrain sensitivity to endogenous satiety signals. This result suggests that oxytocin could be of therapeutic interest to circumvent leptin resistance associated with common forms of obesity.