Inhibitory Mechanism of Signal Transduction through Chicken Leptin Receptor by Suppressor of Cytokine Signaling 3 (SOCS3)

Abstract

Leptin is an adipocyte-derived hormone involved in the regulation of feeding behavior and energy homeostasis in vertebrates. We recently reported that leptin activates the JAK-STAT signaling pathway through the chicken leptin receptor (chLEPR). However, the molecular inhibitory mechanism by suppressor of cytokine signaling 3 (SOCS3), observed in mammalian leptin signaling, has not been elucidated in avian species. Therefore, the role of chicken SOCS3 (chSOCS3) in signal transduction through the chLEPR was analyzed in this study. Leptin increases SOCS3 mRNA expression in chicken hepatoma cells, LMH, and also activates the chSOCS3 gene promoter in the chLEPR-expressing cells. Overexpression of chSOCS3 inhibited leptin-induced signaling by blocking phosphorylation of JAK2 and subsequent activation of STAT3 similar to that observed in mammals. Signaling inhibited by chSOCS3 was not restored in the chLEPR mutated docking site of SOCS3. In addition, mutation of Phe25 in the kinase inhibitory region of chSOCS3 abolished SOCS3 activity via the wild chLEPR. The present study indicates that SOCS3 is a negative feedback regulator of leptin signaling in chickens as well as in mammals. However, the inhibitory mechanism in chickens may differ slightly from that observed in mammals.