TY - JOUR
T1 - FGF21 regulates metabolism and circadian behavior by acting on the nervous system
AU - Bookout, Angie L.
AU - De Groot, Marleen H M
AU - Owen, Bryn M.
AU - Lee, Syann
AU - Gautron, Laurent
AU - Lawrence, Heather L.
AU - Ding, Xunshan
AU - Elmquist, Joel K.
AU - Takahashi, Joseph S.
AU - Mangelsdorf, David J.
AU - Kliewer, Steven A.
N1 - Funding Information:
We thank Y. Zhang, K. Vale and E. Borowicz for help with mouse studies, X. Wang and Y. Wan for tibia measurements, D. Lauzon and C. Lee for in situ hybridization, M. Izumo for Camk2a-Cre mice (University of Texas Southwestern Medical Center), M. Scott for Phox2b-Cre mice (University of Virginia), C. Cummins for advice on glucocorticoid and ACTH assays and all members of the Takahashi, Elmquist and Mango/Kliewer laboratories for critical discussions. This work was supported by US National Institutes of Health grants R01DK067158, P20RR20691 and 1RL1GM084436-01 (to S.A.K. and D.J.M.), U19DK62434 (to J.K.E. and D.J.M.), P01DK088761 and RL1DK081185 (to J.K.E.) and GM007062 (to A.L.B.), the Robert A. Welch Foundation (grant I-1558 to S.A.K. and grant I-1275 to D.J.M.) and the Howard Hughes Medical Institute (to J.S.T. and D.J.M.).
PY - 2013/9
Y1 - 2013/9
N2 - Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; 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 β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. 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 β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-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.
AB - Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; 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 β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues. 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 β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-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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U2 - 10.1038/nm.3249
DO - 10.1038/nm.3249
M3 - Article
C2 - 23933984
AN - SCOPUS:84883778996
SN - 1078-8956
VL - 19
SP - 1147
EP - 1152
JO - Nature medicine
JF - Nature medicine
IS - 9
ER -