Fibroblast growth factor 21 (FGF21) is a potent hormone with antiobesity and antidiabetic effects, and it has been the focus of clinical trials. But how the protein works, especially in vivo, is still mysterious. Paul A. Dutchak et al. (Cell 148, 556–567) now provide important insights into this mechanism. They find that in response to feeding FGF21 is expressed in white adipose tissue, where it acts locally in fat cells to increase peroxisome proliferator–activated receptor-γ (PPAR-γ) activity. PPAR-γ is a key mediator of adipocyte maturation and function, and the team found that FGF21-knockout mice have a mild lipodystrophic phenotype. Although they did not report on such findings, this lipodystrophy in the knockout mice probably indicates that local FGF21-mediated increases in PPAR-γ activity in fat tissue in response to food intake may translate into an acute increase in adipogenesis and adiposity. However, it should be noted that pharmacological treatment with exogenous FGF21 leads to weight loss in rodents and monkeys, indicating that systemic FGF21 is probably acting on many tissues with the overall chronic effect of reduced adiposity.
PPAR-γ is the major target of thiazolidinediones (TZDs), a class of antidiabetic drugs that include rosiglitazone. The authors also found that FGF21-knockout mice are resistant to many, though not all, of both the beneficial and adverse effects of rosiglitazone. Thus, these findings also provide further insight into the mechanism of action of TZDs and perhaps suggest ways to maintain the benefits of these drugs while avoiding their pitfalls.
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