利拉鲁肽对下丘脑 POMC 和 NPY/AgRP 神经元的直接和间接作用——对能量平衡和血糖控制的影响。
Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons - Implications for energy balance and glucose control.
机构信息
The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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 100005, China.
出版信息
Mol Metab. 2019 Oct;28:120-134. doi: 10.1016/j.molmet.2019.07.008. Epub 2019 Jul 31.
OBJECTIVE
The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, stimulates insulin secretion and efficiently suppresses food intake to reduce body weight. As such, liraglutide is growing in popularity in the treatment of diabetes and chronic weight management. Within the brain, liraglutide has been shown to alter the activity of hypothalamic proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. Moreover, the acute activities of POMC and NPY neurons have been directly linked to feeding behavior, body weight, and glucose metabolism. Despite the increased usage of liraglutide and other GLP-1 analogues as diabetic and obesity interventions, the cellular mechanisms by which liraglutide alters the activity of metabolically relevant neuronal populations are poorly understood.
METHODS
In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY neurons for patch-clamp electrophysiology experiments.
RESULTS
We found that liraglutide directly activated arcuate POMC neurons via TrpC5 channels, sharing a similar mechanistic pathway to the adipose-derived peptide leptin. Liraglutide also indirectly increases excitatory tone to POMC neurons. In contrast, liraglutide inhibited NPY/AgRP neurons through post-synaptic GABA receptors and enhanced activity of pre-synaptic GABAergic neurons, which required both TrpC5 subunits and K-ATP channels. In support of an additive role of leptin and liraglutide in suppressing food intake, leptin potentiated the acute effects of liraglutide to activate POMC neurons. TrpC5 subunits in POMC neurons were also required for the intact pharmacological effects of liraglutide on food intake and body weight. Thus, the current study adds to recent work from our group and others, which highlight potential mechanisms to amplify the effects of GLP-1 agonists in vivo. Moreover, these data highlight multiple sites of action (both pre- and post-synaptic) for GLP-1 agonists on this circuit.
CONCLUSIONS
Taken together, our results identify critical molecular mechanisms linking GLP-1 analogues in arcuate POMC and NPY/AgRP neurons with metabolism.
目的
长效胰高血糖素样肽-1 受体 (GLP-1R) 激动剂利拉鲁肽可刺激胰岛素分泌，并有效抑制食欲，从而减轻体重。因此，利拉鲁肽在糖尿病和慢性体重管理治疗中的应用日益广泛。在大脑中，已发现利拉鲁肽可改变下丘脑前阿黑皮素原 (POMC) 和神经肽 Y/Agouti 相关肽 (NPY/AgRP) 神经元的活性。此外，POMC 和 NPY 神经元的急性活性与摄食行为、体重和葡萄糖代谢直接相关。尽管利拉鲁肽和其他 GLP-1 类似物作为糖尿病和肥胖干预措施的使用越来越多，但利拉鲁肽改变与代谢相关神经元群体活性的细胞机制仍知之甚少。
方法
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 POMC 和 NPY 神经元，以便进行膜片钳电生理学实验。
结果
我们发现利拉鲁肽通过 TrpC5 通道直接激活弓状核 POMC 神经元，其机制与脂肪衍生肽瘦素相似。利拉鲁肽还间接增加 POMC 神经元的兴奋性。相比之下，利拉鲁肽通过突触后 GABA 受体抑制 NPY/AgRP 神经元，并增强突触前 GABA 能神经元的活性，这需要 TrpC5 亚基和 K-ATP 通道。支持瘦素和利拉鲁肽在抑制摄食方面具有相加作用，瘦素增强了利拉鲁肽激活 POMC 神经元的急性作用。POMC 神经元中的 TrpC5 亚基也是利拉鲁肽对摄食和体重的完整药理作用所必需的。因此，本研究补充了我们小组和其他小组最近的工作，这些工作强调了增强 GLP-1 激动剂在体内作用的潜在机制。此外，这些数据突出了 GLP-1 激动剂在该回路中的多个作用部位（突触前和突触后）。
结论
总之，我们的研究结果确定了将 GLP-1 类似物与弓状核 POMC 和 NPY/AgRP 神经元中的代谢联系起来的关键分子机制。
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