FGF21 Promotes Thermogenesis by Browning Thermogenic Adipose Tissue during Cold Exposure

The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growth factor 21 (FGF21) emerging as a critical regulator linking environmental stimuli to adipose plasticity and mitochondrial function. However, the precise mechanisms of FGF21 secretion and its specific role in adipose tissue browning and subsequent NST potentiation remain incompletely elucidated.

FGF21 regulates NST via distinct spatiotemporal mechanisms. Acute cold exposure triggers hepatic FGF21 secretion through a β₃-adrenergic-lipolysis-PPARα axis to provide lipid substrates. In contrast, chronic cold adaptation involves adipose-derived FGF21 signaling via the FGFR1/β-Klotho complex, activating the PLCγ-Ca2+-cAMP response element-binding protein pathway to enhance UCP1 expression and mitochondrial biogenesis. Aging and statins impair NST via mitochondrial dysfunction and CoQ₁₀ depletion, inducing compensatory FGF21 upregulation. Clinically, the efficacy of FGF21-based therapies relies on full activation of adipose FGFR1/β-Klotho signaling, as demonstrated by the superiority of full agonists over partial agonists.

FGF21 exhibits dual regulation: hepatic (acute lipid mobilization) and adipose-based (chronic browning); adipose-targeted FGF21 delivery is essential for therapeutic efficacy, and future studies should integrate FGF21 with UCP1-independent pathways (e.g., creatine/succinate cycles) to advance obesity treatment.