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

Summary

FGF21 restores hepatic leptin sensitivity via an adiponectin–STAT1–LEPR pathway and, when combined as a long-acting FGF21/leptin dual agonist, produces superior metabolic benefits in mice without reducing food intake. In human hepatocytes and liver organoids, adiponectin (but not FGF21 directly) rescues LEPRb under lipotoxic stress, reinstating leptin’s suppression of gluconeogenesis and steatosis.

Key Findings

• FGF21 induces adipocyte adiponectin, which activates STAT1 in hepatocytes to upregulate LEPR, reversing hepatic leptin resistance.
• A long-acting FGF21/leptin dual agonist outperformed mono-agonists in preventing weight gain, insulin resistance, hyperglycemia, dyslipidemia, and MASLD in mice without reducing food intake.
• In human primary hepatocytes and liver organoids, adiponectin—but not FGF21 directly—rescued palmitate/oleate-induced LEPRb downregulation, restoring leptin’s suppression of gluconeogenesis and steatosis.

Clinical Implications

Although preclinical, results support developing FGF21/leptin dual agonists for obesity-related multimorbidity (e.g., insulin resistance, dyslipidemia, MASLD). Biomarkers along the adiponectin–STAT1–LEPR axis may guide patient selection and pharmacodynamic monitoring.

Limitations

• Preclinical study; no human clinical efficacy or safety data for the dual agonist.
• Durability and safety of chronic dual-agonism and potential off-target effects remain to be established.
• Generalizability across diverse human metabolic phenotypes is unknown.

Future Directions

First-in-human trials of FGF21/leptin dual agonists with biomarker-guided enrichment (adiponectin–STAT1–LEPR signatures), dose-ranging, and cardio-hepato-renal outcomes; exploration of combination strategies with SGLT2i/GLP-1RA.