FGF-21 is produced by hepatocytes in response to free fatty acid (FFA) stimulation of a
PPAR alpha /RXR dimeric complex (4, 13-15). This situation occurs during starvation, diabetic ketosis,
or following the ingestion of a high-fat/low-carbohydrate or ketogenic diet (5, 14-16). Upon
FGF-21 secretion, white adipose tissue is induced to release FFAs from triglyceride stores. Once
FFAs reach the hepatocytes, they are oxidized and reduced to acetyl-CoA (16). The acetyl-CoA is
recombined into 4-carbon ketone bodies (acetoacetate and beta -hydroxybutyrate), released, and
transported to peripheral tissues for energy generation (5, 15, 16). FGF-21 production is also induced upon differentiation of human or mouse fibroblasts to
adipocytes (17, 18). In adipose tissue, FGF-21 induces glucose uptake by signaling in synergy
with PPAR gamma to increase production of the glucose transporter, GLUT1 (10, 12, 19).
FGF-21
production follows a circadian pattern in mice (20). It diffuses across the blood-brain barrier
and this may facilitate induction of a state of torpor, or decreased activity, in response to
increased FGF-21 (16, 21). These characteristics appear to induce a hibernation-like state during
fasting and short days in winter (22). In diet-induced obese mice and mouse models of
diabetes such as db/db and ob/ob, administration or transgenic overexpression of FGF-21
restores circulating glucose and triglyceride values to near normal and increases insulin
sensitivity (5, 6, 14, 23, 24). In some of these states and in human obesity and type II diabetes,
FGF-21 is already elevated prior to treatment, suggesting that resistance to FGF-21 is possible
(17, 25, 26). Although FGF-21 administration corrects obesity in mice, it is unclear whether the
same benefit would be seen in humans (2, 3, 17, 26-28).
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