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

Research paper by Matthew J MJ Potthoff, Jamie J Boney-Montoya, Mihwa M Choi, Tianteng T He, Nishanth E NE Sunny, Santhosh S Satapati, Kelly K Suino-Powell, H Eric HE Xu, Robert D RD Gerard, Brian N BN Finck, Shawn C SC Burgess, David J DJ Mangelsdorf, Steven A SA Kliewer

Indexed on: 07 Jun '11Published on: 07 Jun '11Published in: Cell Metabolism


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.