Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons.
Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons.
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DOI：
10.1016/j.cmet.2009.09.008
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发表时间：
2009-11
期刊：
影响因子：
29
通讯作者：
Withers DJ
中科院分区：
文献类型：
--
作者：
Al-Qassab H;Smith MA;Irvine EE;Guillermet-Guibert J;Claret M;Choudhury AI;Selman C;Piipari K;Clements M;Lingard S;Chandarana K;Bell JD;Barsh GS;Smith AJ;Batterham RL;Ashford ML;Vanhaesebroeck B;Withers DJ
PI3K信号被认为通过很大程度上未知的机制介导下丘脑前阿黑皮素（POMC）和刺鼠相关蛋白（AgRP）神经元（能量稳态的关键调节因子）中的瘦素和胰岛素作用。我们在这些神经元中失活p110α或p110β PI3K催化亚基，并证明后者在能量稳态调节中起主导作用。在POMC神经元中，p110β失活阻止了胰岛素和瘦素刺激的电生理反应。POMCp110β基因敲除小鼠表现出中枢瘦素抵抗、肥胖增加和饮食诱导的肥胖。相反，p110α缺陷的POMC神经元对瘦素的反应没有被阻断。因此，POMCp110α基因敲除小鼠表现出极轻微的能量稳态异常。同样，在AgRP神经元中，p110β比p110α具有更重要的作用。AgRPp110α基因敲除小鼠表现出正常的能量稳态调节，而AgRPp110β基因敲除小鼠是瘦的，具有增加的瘦素敏感性和对饮食诱导的肥胖的抵抗力。这些结果表明PI3K的p110α和p110β亚型在下丘脑能量调节中具有不同的代谢作用。
PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110α or p110β PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110β inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110β null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110α-deficient POMC neurons. Accordingly, POMCp110α null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110β had a more important role than p110α. AgRPp110α null mice displayed normal energy homeostasis regulation, whereas AgRPp110β null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110α and p110β isoforms of PI3K in hypothalamic energy regulation.
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影响因子：
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