Sun Jia, Gao Yong, Yao Ting, Huang Yiru, He Zhenyan, Kong Xingxing, Yu Kai-Jiang, Wang Rui-Tao, Guo Hongbo, Yan Jianqun, Chang Yongsheng, Chen Hong, Scherer Philipp E, Liu Tiemin, Williams Kevin W
Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Mol Metab. 2016 Aug 18;5(10):882-891. doi: 10.1016/j.molmet.2016.08.007. eCollection 2016 Oct.
Adiponectin receptors (AdipoRs) are located on neurons of the hypothalamus involved in metabolic regulation - including arcuate proopiomelanocortin (Pomc) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. AdipoRs play a critical role in regulating glucose and fatty acid metabolism by initiating several signaling cascades overlapping with Leptin receptors (LepRs). However, the mechanism by which adiponectin regulates cellular activity in the brain remains undefined.
In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify Pomc and NPY/AgRP neurons which express LepRs for patch-clamp electrophysiology experiments.
We found that leptin and adiponectin synergistically activated melanocortin neurons in the arcuate nucleus. Conversely, NPY/AgRP neurons were inhibited in response to adiponectin. The adiponectin-induced depolarization of arcuate Pomc neurons occurred via activation of Phosphoinositide-3-kinase (PI3K) signaling, independent of 5' AMP-activated protein kinase (AMPK) activity. Adiponectin also activated melanocortin neurons at various physiological glucose levels.
Our results demonstrate a requirement for PI3K signaling in the acute adiponectin-induced effects on the cellular activity of arcuate melanocortin neurons. Moreover, these data provide evidence for PI3K as a substrate for both leptin and adiponectin to regulate energy balance and glucose metabolism via melanocortin activity.
脂联素受体（AdipoRs）位于参与代谢调节的下丘脑神经元上，包括弓状前阿黑皮素原（Pomc）神经元和神经肽Y/刺鼠相关肽（NPY/AgRP）神经元。AdipoRs通过启动与瘦素受体（LepRs）重叠的多种信号级联反应，在调节葡萄糖和脂肪酸代谢中起关键作用。然而，脂联素调节大脑细胞活性的机制仍不明确。
为了解决这个问题，我们利用神经元特异性转基因小鼠模型来鉴定表达LepRs的Pomc和NPY/AgRP神经元，用于膜片钳电生理实验。
我们发现瘦素和脂联素协同激活弓状核中的黑皮质素神经元。相反，NPY/AgRP神经元对脂联素产生反应而受到抑制。脂联素诱导的弓状Pomc神经元去极化是通过磷酸肌醇-3-激酶（PI3K）信号通路的激活发生的，与5'AMP激活的蛋白激酶（AMPK）活性无关。脂联素在各种生理葡萄糖水平下也能激活黑皮质素神经元。
我们的结果表明，PI3K信号通路在脂联素对弓状黑皮质素神经元细胞活性的急性诱导作用中是必需的。此外，这些数据为PI3K作为瘦素和脂联素的底物，通过黑皮质素活性调节能量平衡和葡萄糖代谢提供了证据。
