Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis - PubMed (original) (raw)

Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis

Eleni M Domouzoglou et al. Am J Clin Nutr. 2011 Apr.

Abstract

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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Figures

FIGURE 1.

FIGURE 1.

Summary of fibroblast growth factor 21 (FGF21) physiology in mice and humans. In mice, consumption of a ketogenic diet leads to a peroxisome proliferator-activated receptor (PPAR) α–dependent increase of FGF21 in the liver and an increase in serum FGF21 concentrations. FGF21 expression in the liver is also induced by fatty liver disease, obesity, and PPARα ligands in mice. PPARα ligands, such as fenofibrate, also increase FGF21 messenger RNA expression in human hepatocytes. FGF21 interacts with the FGF receptor (FGFR) in the presence of βKlotho in the mouse liver and adipose tissue. This interaction leads to a PPARγ coactivator protein-1α (PGC1α)–dependent up-regulation of fatty acid oxidation and down-regulation of lipid synthesis in the liver. In mouse adipose tissue, the presence of PPARγ ligands leads to the production of FGF21, and the short-term effect of FGF21 results in a decreased expression of lipolytic genes and leads to lower concentrations of circulating free fatty acids (FFA). FGF21-induced phosphorylation of extracellular signal-regulated kinase-1 (ERK) leads to the activation of glucose transporter-1 (Glut-1) and glucose uptake in mouse 3T3-L1 adipocytes and primary human adipocytes. In humans, serum concentrations of FGF21 are higher in diabetes, obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). This effect may be mediated by increased FGF21 liver expression.

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