FGF21 synergizes with leptin to counteract obesity-related metabolic comorbidities by reversing hepatic leptin resistance.

Leptin resistance hinders its therapeutic potential for obesity-related metabolic comorbidities. Here, we show that fibroblast growth factor 21 (FGF21) synergizes with leptin in metabolic regulation by reversing obesity-induced peripheral leptin resistance. FGF21 acts in adipocytes to promote the secretion of adiponectin, which in turn induces the expression of leptin receptors by phosphorylation and activation of the signal transducer and activator of transcription 1 (STAT1) in hepatocytes. Intraperitoneal injection of a long-acting FGF21/leptin dual agonist achieves much more robust pharmacological effects than FGF21 or leptin mono-agonists in protecting mice from diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease without affecting food intake. In human primary hepatocytes and liver organoids, adiponectin but not FGF21 counteracts palmitate/oleate-induced downregulation of leptin receptor b, thereby restoring the effects of leptin in suppressing gluconeogenesis and hepatic steatosis. Thus, FGF21 and leptin dual agonism may represent a promising therapeutic approach for obesity-related multimorbidity through their synergistic and complementary actions in peripheral tissues.