AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons
AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons
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DOI：
10.1172/jci31516
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Withers, Dominic J.
中科院分区：
文献类型：
--
作者：
Claret, Marc;Smith, Mark A.;Withers, Dominic J.
下丘脑腺苷酸活化蛋白激酶（AMPK）是一种重要的能量敏感机制，在能量平衡的调节中对激素和营养物质起反应。然而，涉及的精确神经元群体和细胞机制尚不清楚。长期操纵下丘脑AMPK对能量平衡的影响也是未知的。为了直接解决这些问题，我们产生了POMC α 2KO和AgRP α 2KO小鼠，在前阿黑皮素-（POMC-）和刺鼠相关蛋白表达（AgRP表达）神经元中缺乏AMPK α 2，这是能量稳态的关键调节因子。POMC α 2KO小鼠由于能量消耗减少和食物摄入失调而发展为肥胖，但对瘦素仍然敏感。相比之下，AgRPa 2KO小鼠形成了年龄依赖性瘦表型，对黑皮质素激动剂的敏感性增加。对AMPK α 2缺陷的POMC或AgRP神经元的电生理研究显示，瘦素或胰岛素作用正常，但对细胞外葡萄糖水平的变化没有反应，这表明这些神经元中的葡萄糖敏感信号传导机制与瘦素或胰岛素利用的途径不同。结合POMC α 2KO和AgRP α 2KO小鼠的不同表型，我们的研究结果表明，虽然AMPK在下丘脑功能中起着关键作用，但它并不作为下丘脑内侧基底部能量稳态的一般传感器和整合器。
Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. in contrast, AgRPa2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha 2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.