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

Author

Listed:
  • Sheng Qiu

    (Chongqing Medical University
    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
    Chongqing Medical University)

  • Mengliu Yang

    (Chongqing Medical University)

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.

Suggested Citation

  • Sheng Qiu & Qinan Wu & Hao Wang & Dongfang Liu & Chen Chen & Zhiming Zhu & Hongting Zheng & Gangyi Yang & Ling Li & Mengliu Yang, 2024. "AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47684-9
    DOI: 10.1038/s41467-024-47684-9
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    1. Lin Jiang & Haoran Su & Xiaoyin Wu & Hong Shen & Min-Hyun Kim & Yuan Li & Martin G. Myers & Chung Owyang & Liangyou Rui, 2020. "Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Yasuhiko Minokoshi & Thierry Alquier & Noboru Furukawa & Young-Bum Kim & Anna Lee & Bingzhong Xue & James Mu & Fabienne Foufelle & Pascal Ferré & Morris J. Birnbaum & Bettina J. Stuck & Barbara B. Kah, 2004. "AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus," Nature, Nature, vol. 428(6982), pages 569-574, April.
    3. Putianqi Wang & Ken H. Loh & Michelle Wu & Donald A. Morgan & Marc Schneeberger & Xiaofei Yu & Jingyi Chi & Christin Kosse & Damian Kim & Kamal Rahmouni & Paul Cohen & Jeffrey Friedman, 2020. "A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue," Nature, Nature, vol. 583(7818), pages 839-844, July.
    4. Hongli Li & Yuanzhong Xu & Yanyan Jiang & Zhiying Jiang & Joshua Otiz-Guzman & Jessie C. Morrill & Jing Cai & Zhengmei Mao & Yong Xu & Benjamin R. Arenkiel & Cheng Huang & Qingchun Tong, 2023. "The melanocortin action is biased toward protection from weight loss in mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    5. Seul Ki Kim & Le Trung Tran & Cherl NamKoong & Hyung Jin Choi & Hye Jin Chun & Yong-ho Lee & MyungHyun Cheon & ChiHye Chung & Junmo Hwang & Hyun-Ho Lim & Dong Min Shin & Yun-Hee Choi & Ki Woo Kim, 2023. "Author Correction: Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    6. Lin Jiang & Haoran Su & Xiaoyin Wu & Hong Shen & Min-Hyun Kim & Yuan Li & Martin G. Myers & Chung Owyang & Liangyou Rui, 2020. "Author Correction: Leptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    7. Michael A. Cowley & James L. Smart & Marcelo Rubinstein & Marcelo G. Cerdán & Sabrina Diano & Tamas L. Horvath & Roger D. Cone & Malcolm J. Low, 2001. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus," Nature, Nature, vol. 411(6836), pages 480-484, May.
    8. Su Yang & Huiming Yang & Renbao Chang & Peng Yin & Yang Yang & Weili Yang & Shanshan Huang & Marta A. Gaertig & Shihua Li & Xiao-Jiang Li, 2017. "MANF regulates hypothalamic control of food intake and body weight," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    9. Seul Ki Kim & Le Trung Tran & Cherl NamKoong & Hyung Jin Choi & Hye Jin Chun & Yong-ho Lee & MyungHyun Cheon & ChiHye Chung & Junmo Hwang & Hyun-Ho Lim & Dong Min Shin & Yun-Hee Choi & Ki Woo Kim, 2023. "Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    10. G. J. Morton & D. E. Cummings & D. G. Baskin & G. S. Barsh & M. W. Schwartz, 2006. "Central nervous system control of food intake and body weight," Nature, Nature, vol. 443(7109), pages 289-295, September.
    11. Yuan Fang & Zhi-Yong Shen & Yi-Zhi Zhan & Xiao-Chuang Feng & Ke-Li Chen & Yong-Sheng Li & Hai-Jun Deng & Su-Ming Pan & De-Hua Wu & Yi Ding, 2019. "CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    12. Linghai Yang & G. Stanley McKnight, 2015. "Hypothalamic PKA regulates leptin sensitivity and adiposity," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    13. Jie Xu & Christopher L. Bartolome & Cho Shing Low & Xinchi Yi & Cheng-Hao Chien & Peng Wang & Dong Kong, 2018. "Genetic identification of leptin neural circuits in energy and glucose homeostases," Nature, Nature, vol. 556(7702), pages 505-509, April.
    Full references (including those not matched with items on IDEAS)

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