Induction of leptin resistance by activation of cAMP-Epac signaling.
Induction of leptin resistance by activation of cAMP-Epac signaling.
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DOI：
10.1016/j.cmet.2011.01.016
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发表时间：
2011-03-02
期刊：
影响因子：
29
通讯作者：
Elmquist JK
中科院分区：
文献类型：
--
作者：
Fukuda M;Williams KW;Gautron L;Elmquist JK
瘦素调节能量平衡和葡萄糖稳态。瘦素被发现后不久，人们就确定肥胖通常与瘦素抵抗有关，尽管其分子机制仍有待确定。为了探索瘦素抵抗的潜在机制，我们采用器官型脑切片来鉴定负调节瘦素敏感性的候选信号通路。我们发现，腺苷3′，5′-磷酸（cAMP）水平的升高损害了下丘脑内瘦素激活的多个信号级联。值得注意的是，这种作用不依赖于蛋白激酶A的激活。与此相反，Epac（cAMP调节的小G蛋白Rap 1的鸟嘌呤核苷酸交换因子）的激活足以损害瘦素信号传导，同时诱导SOCS-3表达。Epac激活也减弱了瘦素诱导的下丘脑POMC神经元去极化。最后，Epac激活剂的中枢输注减弱了瘦素的促凋亡作用。因此，下丘脑cAMP-Epac通路的激活足以诱导多个瘦素抵抗指数。
Leptin regulates energy balance and glucose homeostasis. Shortly after leptin was identified, it was established that obesity is commonly associated with leptin resistance, though the molecular mechanisms remain to be identified. To explore potential mechanisms of leptin resistance, we employed organotypic brain slices to identify candidate signaling pathways that negatively regulate leptin sensitivity. We found that elevation of adenosine 3′, 5′-monophosphate (cAMP) levels impairs multiple signaling cascades activated by leptin within the hypothalamus. Notably, this effect is independent of protein kinase A activation. In contrast, activation of Epac, a cAMP-regulated guanine nucleotide exchange factor for the small G protein Rap1, was sufficient to impair leptin signaling with concomitant induction of SOCS-3 expression. Epac activation also blunted leptin-induced depolarization of hypothalamic POMC neurons. Finally, central infusion of an Epac activator blunted the anorexigenic actions of leptin. Thus, activation of hypothalamic cAMP-Epac pathway is sufficient to induce multiple indices of leptin resistance.
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