Journal
NATURE MEDICINE
Volume 19, Issue 9, Pages 1147-1152Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3249
Keywords
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Funding
- US National Institutes of Health [R01DK067158, P20RR20691, 1RL1GM084436-01, U19DK62434, P01DK088761, RL1DK081185, GM007062]
- Robert A. Welch Foundation [I-1558, I-1275]
- Howard Hughes Medical Institute
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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, FGFR2c or FGFR3c) in complex with beta-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, which are all features of the adaptive starvation response. These effects are mediated through beta-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding beta-Klotho (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.
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