This study evaluated whether FGF21 reverses peripheral leptin resistance in obesity and tested a long-acting FGF21/leptin dual agonist vs. mono-agonists in diet-induced obese mice, plus mechanistic validation in human primary hepatocytes and liver organoids.
The FGF21/leptin dual agonist outperformed either mono-agonist in reducing diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and metabolic-dysfunction-associated steatotic liver disease without altering food intake. Mechanistically, FGF21 stimulates adipocyte adiponectin secretion → hepatic leptin receptor (LepRb) upregulation via STAT1 phosphorylation; adiponectin (not FGF21 directly) reversed palmitate/oleate-induced LepRb downregulation in human hepatocytes, restoring leptin-mediated suppression of gluconeogenesis and steatosis.
Preclinical mouse data dominate; human evidence is limited to primary hepatocytes and liver organoids (no clinical trial). The dual agonist construct is not yet tested in humans. Food intake was unaffected, so the weight-loss mechanism in vivo warrants further clarification.
An FGF21/leptin dual agonist approach may one day address obesity-related multimorbidity (diabetes, dyslipidemia, steatotic liver disease) simultaneously by restoring hepatic leptin sensitivity. Clinicians should watch for early-phase trials of FGF21/leptin co-targeting agents, particularly in patients with obesity-related metabolic comorbidities who are leptin-resistant.
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