Homeostasis of glucose and lipid metabolism during physiological responses to a simulated hypoxic high altitude environment

Yi Lin, Bingyu Li, Xinying Shi, Yangkang Chen, Shengkai Pan, Zhenzhen Lin, Zhongru Gu, Frank Hailer, Li Hu () and Xiangjiang Zhan ()
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Yi Lin: Chinese Academy of Sciences
Bingyu Li: Chinese Academy of Sciences
Xinying Shi: Chinese Academy of Sciences
Yangkang Chen: Chinese Academy of Sciences
Shengkai Pan: Chinese Academy of Sciences
Zhenzhen Lin: Chinese Academy of Sciences
Zhongru Gu: Chinese Academy of Sciences
Frank Hailer: Chinese Academy of Sciences
Li Hu: Chinese Academy of Sciences
Xiangjiang Zhan: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Homeostasis facilitates maintenance of physiological processes despite extrinsic fluctuations. In aerobic organisms, homeostasis is mainly fueled by metabolism of glucose and lipids, and requires oxygen as a metabolic substrate. Lack of oxygen can therefore trigger an imbalance of homeostasis in vivo. How animals living at high altitude hypoxic conditions can maintain homeostasis between the two types of metabolism remains largely unknown. Here, we establish a ‘falconized’ mouse model based on an adaptive EPAS1 genetic variant identified from saker falcons (Falco cherrug) on the Qinghai-Tibet Plateau (QTP). We show that homeostasis between glucose and lipid metabolism in the liver under chronic hypoxia is maintained in male falconized mice. This homeostasis is mediated by genetic factors and behavioral plasticity, resulting in higher survival rates even under acute hypoxia than wild type mice. Our study highlights a key role of metabolic homeostasis maintenance for survival in extreme environments, and provides potential targets for the treatment of associated metabolic diseases.

Date: 2025
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DOI: 10.1038/s41467-025-64110-w

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