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; Wenwei Hu

doi:10.1038/s41467-024-44924-w

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, Wenwei Hu

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	627
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44924-w
State	Published - Dec 2024

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-44924-w

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title = "Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice",

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.",

author = "Xue Yang and Jianming Wang and Chang, {Chun Yuan} and Fan Zhou and Juan Liu and Huiting Xu and Maria Ibrahim and Maria Gomez and Guo, {Grace L.} and Hao Liu and Zong, {Wei Xing} and Wondisford, {Fredric E.} and Xiaoyang Su and Eileen White and Zhaohui Feng and Wenwei Hu",

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year = "2024",

month = dec,

doi = "10.1038/s41467-024-44924-w",

language = "English (US)",

volume = "15",

journal = "Nature communications",

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T1 - Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice

AU - Yang, Xue

AU - Wang, Jianming

AU - Chang, Chun Yuan

AU - Zhou, Fan

AU - Liu, Juan

AU - Xu, Huiting

AU - Ibrahim, Maria

AU - Gomez, Maria

AU - Guo, Grace L.

AU - Liu, Hao

AU - Zong, Wei Xing

AU - Wondisford, Fredric E.

AU - Su, Xiaoyang

AU - White, Eileen

AU - Feng, Zhaohui

AU - Hu, Wenwei

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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

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