ENHANCING LEPTIN RESPONSE BY PREVENTING SH2-CONTAINING PHOSPHATASE 2 INTERACTION WITH OB RECEPTOR

Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR), Serum leptin levels are chronically elevated in obese humans, suggesting that obesi ty may be associated with leptin resistance and the inability to gener ate an adequate ObR response. Evidence suggests that transcriptional a ctivation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediate s leptin's action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing p hosphatase 2 (SHP-2) and demonstrate that Tyr(986) within the ObR cyto plasmic domain is essential to mediate phosphorylation of SHP-2 and bi nding of SHP-2 to ObR. Surprisingly, mutation of Tyr(986) to Phe, whic h abrogates SHP-2 phosphorylation and binding to the receptor, dramati cally increases gene induction mediated by STAT3. Our findings indicat e that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the in teraction of SHP-2 with ObR could overcome leptin resistance by boosti ng leptin's weight-reducing effects in obese individuals.