Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice

Xue Yang, Jianming Wang, Chun-Yuan Chang, Fan Zhou, Juan Liu, Huiting Xu, Maria Ibrahim, Maria Gomez, Grace L. Guo, Hao Liu, Wei-Xing Zong, Fredric E. Wondisford, Xiaoyang Su, Eileen White, Zhaohui Feng () and Wenwei Hu ()
Additional contact information
Xue Yang: Rutgers University
Jianming Wang: Rutgers University
Chun-Yuan Chang: Rutgers University
Fan Zhou: Rutgers University
Juan Liu: Rutgers University
Huiting Xu: Rutgers-Robert Wood Johnson Medical School
Maria Ibrahim: Rutgers University
Maria Gomez: Rutgers University
Grace L. Guo: Rutgers University
Hao Liu: Rutgers School of Public Health
Wei-Xing Zong: Rutgers University
Fredric E. Wondisford: Rutgers-Robert Wood Johnson Medical School
Xiaoyang Su: Rutgers-Robert Wood Johnson Medical School
Eileen White: Rutgers University
Zhaohui Feng: Rutgers University
Wenwei Hu: Rutgers University

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

Abstract: Abstract Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.

Date: 2024
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DOI: 10.1038/s41467-024-44924-w

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