Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction

Abstract GDF15 and FGF21, stress-responsive cytokines primarily secreted from liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effect of the hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21 respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. Interestingly, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, but FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and splicing of XBP1s, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids, GDF15 overexpression also upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Taken together, excess FFAs flooding the liver resulted in a gradual increase of β-oxidation-derived reactive oxygen species and ER stress, suggesting that GDF15 enhanced this pathway and induced the expression of FGF21. The GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.