Pluto Bioinformatics

GSE135881: Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

Bulk RNA sequencing

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism increases plasma bile acid levels. We hypothesized that GcgR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole body and liver-specific FXR knockout (FXRliver) mice. Chronic GcgR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21 and Fxr whole body or liver-specific knockout (liver) mice failed to reduce body weight (BW) when compared to wildtype (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not FXRliver mice. GcgR agonism increased [14C]-palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from FXRliver mice. Our data clearly demonstrate that control of whole body energy expenditure by GcgR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in the therapy of metabolic disorders. SOURCE: Mark,Emile,Pepin (pepinme@uab.edu) - Adam Wende Laboratory University of Alabama at Birmingham