Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Metab. 2011 Mar 2;13(3):331-9. doi: 10.1016/j.cmet.2011.01.016.
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.
瘦素调节能量平衡和葡萄糖稳态。瘦素被发现后不久，人们就发现肥胖通常与瘦素抵抗有关，但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'-单磷酸（cAMP）水平的升高会损害瘦素在下丘脑内激活的多种信号级联反应。值得注意的是，这种效应不依赖于蛋白激酶 A 的激活。相比之下，cAMP 调节的 Ras 相关蛋白 1（Rap1）的鸟嘌呤核苷酸交换因子 Epac 的激活足以损害瘦素信号转导，并伴随 SOCS-3 表达的诱导。Epac 的激活也削弱了瘦素诱导的下丘脑 POMC 神经元去极化。最后，中枢内注入 Epac 激活剂可削弱瘦素的厌食作用。因此，下丘脑 cAMP-Epac 通路的激活足以诱导多种瘦素抵抗指标。
