Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
Key Laboratory of Medical Diagnostics of Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.
Nat Commun. 2024 Apr 20;15(1):3377. doi: 10.1038/s41467-024-47684-9.
Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.
锌-α2-糖蛋白（AZGP1）已被牵涉到外周代谢中；然而，其在调节大脑能量代谢中的作用，特别是在 POMC 神经元中，仍不清楚。在这里，我们表明 POMC 神经元中的 AZGP1 在控制全身代谢中起着关键作用。高脂肪饮食条件下 POMC 神经元特异性过表达 Azgp1 可减少能量摄入、提高能量消耗、提高外周组织瘦素和胰岛素敏感性、减轻肝脂肪变性，并促进脂肪组织褐变。相反，POMC 神经元中诱导性缺失 Azgp1 的小鼠表现出相反的代谢表型，对饮食诱导的肥胖表现出更高的易感性。值得注意的是，下丘脑中 AZGP1 信号的增加会提高 STAT3 磷酸化并增加 POMC 神经元的兴奋性。在机制上，AZGP1 通过与酰基甘油激酶（AGK）相互作用增强瘦素-JAK2-STAT3 信号，从而阻止其泛素化降解。总之，这些结果表明，AZGP1 通过作用于下丘脑 POMC 神经元在调节能量平衡和葡萄糖/脂质代谢中起着关键作用。
