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Investigation of signaling cascades and transcriptional regulation associated with FGF1 action in metabolic tissues

Subject Area Endocrinology, Diabetology, Metabolism
Biochemistry
Nephrology
Term from 2015 to 2019
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 278992880
 
Final Report Year 2022

Final Report Abstract

Fibroblast growth factor 1 (FGF1) has an established role in adaptive adipose remodeling. Mice lacking FGF1 develop a more aggressive diabetic phenotype in response to a dietary challenge (high fat diet, HFD) that is, in part, attributed to a failure to appropriately remodel adipose tissue. In addition, FGF1 expression in adipose tissue is controlled by PPARg and robustly induced in the fed state and upon HFD feeding. Previously, our lab showed that peripheral delivery of FGF1 rapidly lowers blood glucose levels in diabetic mouse models in an adipose FGF receptor (FGFR) 1-dependent manner, however the underlying mechanism(s) is not understood. In this study, we show that FGF1 acutely suppresses hepatic glucose production (HGP), and that this suppression is dependent on the anti-lipolyic function of adipose FGF1-FGFR1 signaling. Moreover, the dependence of the FGF1-mediated HGP regulation on gluconeogenic substrates, and the changes in the hepatic levels of gluconeogenic metabolites suggested that rFGF1 uses a pathway similar to insulin for indirect regulation of HGP. Indeed, we observed that FGF1 suppresses lipolysis by inhibiting the cAMP-PKA pathway, which is the molecular hub for the hormonal control of lipolysis. Unlike the insulin dependent suppression of cAMP by activating PDE3B, we found that FGF1 depends on PDE4D for its anti-lipolytic actions, suggesting the existence of at least two evolutionally parallel pathways to regulate adipose lipolysis and HGP. In adipocytes, FGF1 lowers cAMP levels and inhibits PKA activity, subsequently decreasing HSL phosphorylation and recruitment to lipid droplets in a PDE4-dependent manner. In vivo inhibition of PDE4 abolishes the FGF1-induced suppression of lipolysis and downregulation of blood glucose levels, suggesting that both the anti-lipolytic and antidiabetic effects of FGF1 are PDE4- dependent. In line with PDE4 inhibition in vivo, the effect of FGF1 on blood glucose levels was abrogated in PDE4D knockout mice suggesting that PDE4D is required for regulation of lipolysis and blood glucose by FGF1. Activation of PDE4D by FGF1 is via phosphorylation of an N-terminal residue on PDE4D (pS44) that is vital for PDE4D activity. Moreover, via generation of adipose specific expression AAVs, we have showed that expression of WT PDE4D but not phospho-site mutant PDE4D (S44A) relieved insulin resistance and lowered blood glucose levels. We also show that this phosphorylation site is regulated by feeding/fasting cycles indicating the involvement of this site on normal physiology. Our study unraveled FGF1/PDE4D axis as a novel antilipolytic pathway that regulates HGP and showed that modulation of FGF1/PDE4D pathway in vivo has great potential to target type-2 diabetes.

 
 

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