Fibroblast growth factor 21 (FGF21) was originally identified as a member of the FGF family in homology studies and is a member of the endocrine FGF subfamily that lacks heparin binding domains and is released into the circulation. A potential role as a metabolic regulator emerged when FGF21 was shown to increase glucose uptake in adipocytes. Subsequently, marked elevations in FGF21 expression were observed in mice that ate a ketogenic diet and when fasting, which suggests that FGF21 expression plays a role in the adaptation to metabolic states that require increased fatty acid oxidation. Consistent with this evidence, FGF21 knockout mice were not able to respond appropriately to consumption of a ketogenic diet. FGF21 expression is downstream of peroxisome proliferator-activated receptor (PPAR) α in the liver and PPARγ in adipose tissue. FGF21 concentrations are higher in both rodent and human obesity, and recent data suggest that obesity may be an FGF21-resistant state. Recent data increasingly suggest that FGF21 is an important metabolic regulator that may have potential clinical implications
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