Hypothalamic PKA regulates leptin sensitivity and adiposity.
Hypothalamic PKA regulates leptin sensitivity and adiposity.
复制标题
DOI：
10.1038/ncomms9237
复制
发表时间：
2015-09-18
影响因子：
16.6
通讯作者：
McKnight GS
中科院分区：
文献类型：
--
作者：
Yang L;McKnight GS
缺乏环腺苷酸依赖性蛋白激酶A（PKA）的RIIβ调节亚基的小鼠表现出减少的肥胖和对饮食诱导的肥胖的抵抗力。在这里，我们表明，RIIβ基因敲除（KO）小鼠对瘦素对摄食和能量代谢的影响具有增强的敏感性。在施用低剂量的瘦素后，下丘脑JAK/STAT 3信号传导的持续时间增加，导致增强的POMC mRNA诱导。与JAK/STAT 3激活延长一致，我们发现瘦素受体信号传导的负反馈调节因子Socs 3在RIIβ KO小鼠的下丘脑中被抑制。在禁食期间，RIIβ-PKA被激活，这与CREB磷酸化的增加相关。在禁食的RIIβ KO下丘脑中不存在CREB磷酸化的增加。选择性抑制AgRP神经元中的PKA活性部分地再现了RIIβ KO小鼠的消瘦和对饮食诱导的肥胖的抵抗。我们的研究结果表明，RIIβ-PKA调节瘦素受体信号传导的持续时间，从而调节对瘦素的分解代谢反应的幅度。 缺乏RIIβ（蛋白激酶A的调节亚基）的小鼠是瘦的，并且对饮食诱导的肥胖有抵抗力。在这里，作者表明RIIβ调节瘦素敏感性，作为下丘脑中瘦素反应性和瘦素信号传导持续时间的生理制动器。
Mice lacking the RIIβ regulatory subunit of cyclic AMP-dependent protein kinase A (PKA) display reduced adiposity and resistance to diet-induced obesity. Here we show that RIIβ knockout (KO) mice have enhanced sensitivity to leptin's effects on both feeding and energy metabolism. After administration of a low dose of leptin, the duration of hypothalamic JAK/STAT3 signalling is increased, resulting in enhanced POMC mRNA induction. Consistent with the extended JAK/STAT3 activation, we find that the negative feedback regulator of leptin receptor signalling, Socs3, is inhibited in the hypothalamus of RIIβ KO mice. During fasting, RIIβ–PKA is activated and this correlates with an increase in CREB phosphorylation. The increase in CREB phosphorylation is absent in the fasted RIIβ KO hypothalamus. Selective inhibition of PKA activity in AgRP neurons partially recapitulates the leanness and resistance to diet-induced obesity of RIIβ KO mice. Our findings suggest that RIIβ–PKA modulates the duration of leptin receptor signalling and therefore the magnitude of the catabolic response to leptin. Mice lacking RIIβ, a regulatory subunit of protein kinase A, are lean and resistant to diet-induced obesity. Here, the authors show that RIIβ regulates leptin sensitivity, acting as a physiological brake on leptin responsiveness and the duration of leptin signalling in the hypothalamus.