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 obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin’s action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr(986) within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr(986) to Phe, which abrogates SHP-2 phosphorylation and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin’s weight-reducing effects in obese individuals.

瘦素（Leptin）是一种脂肪细胞衍生的细胞因子，可通过与其Ob受体（Ob receptor, ObR）结合调节食物摄入与体重。肥胖人群的血清瘦素水平长期升高，这提示肥胖可能与瘦素抵抗以及无法产生足够的ObR应答相关。有证据表明，下丘脑中由信号转导与转录激活因子3（STAT3，signal transducer and activator of transcription）介导的靶基因转录激活是介导瘦素发挥作用的关键通路。本研究报道，ObR激活可诱导含SH2结构域的磷酸酶2（SHP-2，SH2-containing phosphatase 2）这种酪氨酸磷酸酶发生酪氨酸磷酸化，并证实ObR胞质结构域内的Tyr(986)位点对于介导SHP-2的磷酸化以及SHP-2与ObR的结合至关重要。令人意外的是，将Tyr(986)位点突变为苯丙氨酸（Phe）可消除SHP-2的磷酸化及其与受体的结合，却显著增强了STAT3介导的基因诱导效应。本研究结果表明，SHP-2是ObR激活后STAT3介导的基因诱导的负调控因子，同时提出了一种可能性：阻断SHP-2与ObR的相互作用，可通过增强瘦素在肥胖个体中的减重效应来克服瘦素抵抗。