AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation

Sheng Qiu, Qinan Wu, Hao Wang, Dongfang Liu, Chen Chen, Zhiming Zhu, Hongting Zheng, Gangyi Yang (), Ling Li () and Mengliu Yang ()
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Sheng Qiu: Chongqing Medical University
Qinan Wu: The Affiliated Dazu Hospital of Chongqing Medical University
Hao Wang: Chongqing Medical University
Dongfang Liu: Chongqing Medical University
Chen Chen: University of Queensland
Zhiming Zhu: Third Military Medical University
Hongting Zheng: Third Military Medical University
Gangyi Yang: Chongqing Medical University
Ling Li: Chongqing Medical University
Mengliu Yang: Chongqing Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47684-9

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