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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 PPAR\u03b1, a master regulator of lipid metabolism, leading to the downregulation of a group of PPAR\u03b1 target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPAR\u03b1 by fenofibrate, a PPAR\u03b1 agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. 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