TY - JOUR
T1 - FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway
AU - Potthoff, Matthew J.
AU - Boney-Montoya, Jamie
AU - Choi, Mihwa
AU - He, Tianteng
AU - Sunny, Nishanth E.
AU - Satapati, Santhosh
AU - Suino-Powell, Kelly
AU - Xu, H. Eric
AU - Gerard, Robert D.
AU - Finck, Brian N.
AU - Burgess, Shawn C.
AU - Mangelsdorf, David J.
AU - Kliewer, Steven A.
N1 - Funding Information:
We thank Bruce Spiegelman for the PGC-1α fl/fl mice; Marc Montminy for the Ad-CRE-luc adenovirus and antibodies; Ruth Yu and Michael Downes for microarray studies; Joao Duarte, Xunshan Ding, and Jessica Mullens for technical assistance; and Xiarong Fu for GC-MS support. This research was supported by the Howard Hughes Medical Institute (D.J.M.); NIH grants DK067158 (S.A.K. and D.J.M), U19DK62434 (D.J.M.), DK078187 (B.N.F.), and DK078184 and DK076269 (S.C.B.); and the Robert A. Welch Foundation (I-1275 to D.J.M. and I-1588 to S.A.K.).
PY - 2011/6/8
Y1 - 2011/6/8
N2 - Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.
AB - Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.
UR - https://www.scopus.com/pages/publications/79958066536
U2 - 10.1016/j.cmet.2011.03.019
DO - 10.1016/j.cmet.2011.03.019
M3 - Article
C2 - 21641554
AN - SCOPUS:79958066536
SN - 1550-4131
VL - 13
SP - 729
EP - 738
JO - Cell metabolism
JF - Cell metabolism
IS - 6
ER -