IDENTIFICATION OF SOCS-3 AS A POTENTIAL MEDIATOR OF CENTRAL LEPTIN RESISTANCE

Leptin affects food intake and body weight by actions on the hypothala mus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peri pheral leptin administration to ob/ob, but not db/db mice, rapidly ind uced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-5. A leptin-dependent increase of SCCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long for m. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked lep tin-induced signal transduction. Expression of SOCS-3 mRNA in the arcu ate and dorsomedial hypothalamic nuclei is increased in A(y)/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediat or of leptin resistance in obesity.