The role of SOCS-3 in leptin signaling and leptin resistance

We earlier demonstrated that leptin induces expression of SOCS-3 mRNA in th e hypothalamus. Furthermore, transfection data suggest that SOCS-3 is an in hibitor of leptin signaling. However, little is known about the regulation of SOCS-3 expression by leptin and the mechanism by which SOCS-3 inhibits l eptin action. We here show that in CHO cells stably expressing the long for m of the leptin receptor (CHO-OBRl), leptin induces transient expression of endogenous SOCS-3 mRNA but not of CIS, SOCS-1, or SOCS-2 mRNA. SOCS-3 prot ein levels were maximal after 2-3 h of leptin treatment and remained elevat ed at 20 h. Furthermore, in leptin-pretreated CHO-OBRl cells, proximal lept in signaling was blocked for more than 20 h after pretreatment, thus correl ating with increased SOCS-3 expression. Leptin pretreatment did not affect cell surface expression of leptin receptors as measured by I-125-Peptin bin ding assays. In transfected COS cells, forced expression of SOCS-3 results in inhibition of leptin-induced tyrosine phosphorylation of JAK2. Finally, JAK2 co-immunoprecipitates with SOCS-3 in lysates from leptin-treated COS c ells. These results suggest that SOCS-3 is a leptin-regulated inhibitor of proximal leptin signaling in vivo. Excessive SOCS-3 activity in leptin-resp onsive cells is therefore a potential mechanism for leptin resistance, a ch aracteristic feature in human obesity.