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-Jenkins, Grace L. Guo, Hao Liu, Wei‐Xing Zong, Fredric E. Wondisford, Xiaoyang Su, Eileen White, Zhaohui Feng, Wenwei Hu
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.