FGF21 regulates circadian behavior and metabolism by acting on the nervous system

Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism, and repress growth(1); however the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell surface receptor composed of one of three FGF receptors (FGFR1c, 2c, or 3c) in complex with β-Klotho(2-4), a single-pass transmembrane protein that is enriched in metabolic tissues(5). Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity, and alters circadian behavior, all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus (SCN) of the hypothalamus and the dorsal vagal complex (DVC) of the hindbrain. Mice lacking the β-Klotho gene (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin, and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.