| Literature DB >> 34986332 |
Gencer Sancar1, Sihao Liu1, Emanuel Gasser1, Jacqueline G Alvarez1, Christopher Moutos1, Kyeongkyu Kim1, Tim van Zutphen2, Yuhao Wang1, Timothy F Huddy1, Brittany Ross1, Yang Dai1, David Zepeda1, Brett Collins1, Emma Tilley1, Matthew J Kolar3, Ruth T Yu1, Annette R Atkins1, Theo H van Dijk2, Alan Saghatelian3, Johan W Jonker2, Michael Downes4, Ronald M Evans5.
Abstract
Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.Entities:
Keywords: FGF1; PDE4; cAMP; hepatic glucose production; insulin; lipolysis; type 2 diabetes
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Year: 2022 PMID： 34986332 PMCID： PMC8863067 DOI： 10.1016/j.cmet.2021.12.004
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287