Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine

FGF21 is a potent metabolic regulator of energy balance, body composition, lipid metabolism, and glucose homeostasis. Initial studies reported that it was increased by fasting and the associated increase in ketones, but more recent work points to the importance of dietary protein and sensing of essential amino acids in FGF21 regulation. For example, dietary restriction of methionine produces a rapid transcriptional activation of hepatic FGF21 that results in a persistent 5- to 10-fold increase in serum FGF21. Although FGF21 is a component of a complex transcriptional program activated by methionine restriction (MR), loss-of-function studies show that FGF21 is an essential mediator of the resulting effects of the MR diet on energy balance, remodeling of adipose tissue, and enhancement of insulin sensitivity. These studies also show that FGF21 signaling in the brain is required for the MR diet-induced increase in energy expenditure (EE) and reduction of adiposity. Collectively, the evidence supports the view that the liver functions as a sentinel to detect and respond to changes in dietary amino acid composition, and that the resulting mobilization of hepatic FGF21 is a key element of the homeostatic response. These findings raise the interesting possibility that therapeutic diets could be developed that produce sustained, biologically effective increases in FGF21 by nutritionally modulating its transcription and release.