FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway

Matthew J. Potthoff, Jamie Boney-Montoya, Mihwa Choi, Tianteng He, Nishanth E. Sunny, Santhosh Satapati, Kelly Suino-Powell, H. Eric Xu, Robert D. Gerard, Brian N. Finck, Shawn C. Burgess, David J. Mangelsdorf, Steven A. Kliewer

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196 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)729-738
Number of pages10
JournalCell metabolism
Volume13
Issue number6
DOIs
StatePublished - Jun 8 2011

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    Potthoff, M. J., Boney-Montoya, J., Choi, M., He, T., Sunny, N. E., Satapati, S., Suino-Powell, K., Xu, H. E., Gerard, R. D., Finck, B. N., Burgess, S. C., Mangelsdorf, D. J., & Kliewer, S. A. (2011). FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell metabolism, 13(6), 729-738. https://doi.org/10.1016/j.cmet.2011.03.019