Role of FGF21 and GCN2 in mediating the metabolic response to dietary protein restriction

FGF21 is an endocrine signal of protein restriction (PR) and prior data implicate the General Control Nonderepressible 2 (GCN2) kinase as the amino acid sensor linking PR to FGF21 induction. Therefore, we hypothesized that GCN2-deficient mice would fail to respond to reduced dietary protein intake and consequently recapitulate the phenotype of FGF21-deficient mice.

C57BL/6J mice (WT), FGF21- and GCN2-deficient mice were fed a control or low protein (LP) diet that was isocaloric by equally varying protein [18% (control) and 4% (LP) of energy] and carbohydrate content while keeping fat content constant. This was offered for 6 months, with behavioral, metabolic and tissue endpoints measured.

In all cases FGF21-deficient mice failed to respond to the LP diet with changes in food intake, energy expenditure, body weight and metabolic gene expression. We also discover that GCN2 plays a critical but transient role in the induction of FGF21. Circulating FGF21 was increased above 8 ng/ml in WT-mice on LP diet for 6 months, whereas the induction of FGF21 by LP diet is markedly blunted in GCN2-deficient mice, which also replicate the phenotype of FGF21-deficient mice in short-term. However, FGF21 levels eventually rose in GCN2-KO mice, an effect that was associated with the appearance of metabolic responses to PR.

Thus, the delayed response to PR in GCN2-deficient mice is explained by the delayed increase in circulating FGF21. These data implicate FGF21 as the first known hormone that is essential for the metabolic response to PR and GCN2 as a unique part of this mechanism.