Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein
Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein
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DOI：
10.1007/s00360-011-0637-4
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
A. Tups;S. Stöhr;M. Helwig;P. Barrett;E. Król;J. Schachtner;J. Mercer;M. Klingenspor
中科院分区：
文献类型：
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作者：
A. Tups;S. Stöhr;M. Helwig;P. Barrett;E. Król;J. Schachtner;J. Mercer;M. Klingenspor
西伯利亚仓鼠Photopus sungorus经历了瘦素敏感性和体重调节的显著季节性周期，但其分子机制和与人类瘦素不敏感的相关性尚不清楚。在这里，我们表明，与长日长(LD)相比，在短日长(SD)的仓鼠中，瘦素能更大程度地刺激下丘脑中磷酸化STAT3的核转位。有趣的是，瘦素对STAT3的影响似乎部分限于与细胞表面相关的磷酸化STAT3的核转位，而不是STAT3的磷酸化。下丘脑中磷酸化ERK细胞的数量不受光周期或瘦素的影响。然而，在ERK磷酸化附近，下丘脑SH2酪氨酸磷酸酶(SHP2)和小生长因子受体结合蛋白(Grb2)作为SOCS3与瘦素受体(LRB)相关Tyr985结合的竞争性负调节因子，在SD组比LD组增加。我们的发现表明，瘦素激活STAT3可能依赖于刺激的SHP2/Grb2和抑制的SOCS3对LRB相关Tyr985的竞争结合水平的相互作用。这一假设机制可能代表了季节性诱导的瘦素敏感性调节的分子一致性，并可能应用于研究其他啮齿动物模型的瘦素敏感性。
The Siberian hamster,Phodopus sungorus, undergoes a striking seasonal cycle of leptin sensitivity and body weight regulation, but the molecular mechanism and relevance to human leptin insensitivity are unknown. Here we show that nuclear translocation ofphospho-STAT3 in the hypothalamus is rapidly stimulated by leptin to a greater extent in hamsters held in short-day length (SD) as compared to long-day length (LD). Intriguingly, effects of leptin on STAT3 appeared to be in part limited to nuclear translocation ofphospho-STAT3 associated with the cell surface rather than phosphorylation of STAT3. The number ofphospho-ERK cells within the hypothalamus was unaffected by either photoperiod or leptin. However, proximal to ERK phosphorylation, hypothalamic SH2-containing tyrosine phosphatase (SHP2) and the small growth factor receptor-binding protein (GRB2), which act as competitive negative modulators on binding of SOCS3 to leptin receptor (LRb)-associated Tyr985, were increased in SD compared to LD. Our findings suggest that activation of STAT3 by leptin may be dependent on interaction of stimulatory SHP2/GRB2 as well as inhibitory SOCS3 on the level of competitive binding to LRb-associated Tyr985. This hypothetical mechanism may represent the molecular identity of seasonally induced adjustments in leptin sensitivity and may be applied to investigating leptin sensitivity in other rodent models.