Glucagon-Receptor Signaling Regulates Mitochondrial Bioenergetics via Hepatic Farnesol X Receptor

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss. We have identified that the hepatic Farnesol X Receptor (FXR) plays an important role in an anti-obesogenic effect of glucagon receptor (GcgR) agonism. Chronic administration of IUB288, a potent GcgR agonist, significantly reduced diet-induced obesity (DIO) in wild type (WT, 17%) mice compared to (FXR^∆liver, 6%) liver-specific FXR knock-out mice. Weight loss was associated with increased energy expenditure (p<0.05) and fat oxidation (reduced RQ, p<0.05). We hypothesized that GcgR agonism alters mitochondrial bioenergetics, at least in part, through hepatic FXR signaling. IUB288 treatment increased body temperature (p<0.05) and [¹⁴C]-palmitate oxidation capacity of liver homogenate (p<0.05) to a greater extent in DIO WT mice than in FXR^∆liver mice. RNA-Seq analysis of DIO liver samples revealed that the mitochondrial oxidative phosphorylation pathway, fatty acid metabolism, and bile acid metabolism were enriched in WT treated with IUB288, but not in FXR^∆liver mice. Liver slices isolated from WT mice treated with IUB288 for two days significantly increased state 3 respiration rates compared to FXR^∆liver mice using high resolution respirometry. Respiration was increased utilizing both carbohydrate (pyruvate, malate, glutamate, and succinate) and lipid substrates (palmitoyl-carnitine), suggesting GcgR-agonism modulates hepatic mitochondrial respiration via FXR. Our study elucidates a molecular mechanism of the anti-obesogenic effect of GcgR signaling. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in therapeutic strategies for multiple components of the metabolic syndrome.