Glucagon Receptor Signaling Regulates Energy Metabolism via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

Abstract

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 glucagon receptor (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 () mice. Chronic GCGR agonist (IUB288) administration in diet-induced obese (DIO) , and whole-body or liver-specific knockout () mice failed to reduce body weight when compared with wild-type (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not mice. GCGR agonism increased [C]palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from 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.

Energy Requirement Is Higher During Weight-Loss Maintenance in Adults Consuming a Low- Compared with High-Carbohydrate Diet

“…Hormonal changes accompanying a low-carbohydrate diet may mediate, to some degree, several of these components. Reduced insulin and ghrelin concentrations may increase energy expenditure in part through activation of brown-adipose tissue activity ( 22 , 23 ), whereas high glucagon may increase energy expenditure through other mechanisms ( 24 , 25 ). The lower leptin concentration on the low-carbohydrate diet ( 8 ) – a predictor of good long-term weight-loss maintenance ( 26–28 ) – may indicate improved hormone sensitivity ( 29 ).…”

Global Transcriptomic Analysis of Zebrafish Glucagon Receptor Mutant Reveals Its Regulated Metabolic Network

“…Beyond suppressing hyperglycemia, disruption of GCGR also leads to increased insulin sensitivity, hypoglycemia, hyperglucagonemia, hyperaminoacidemia, increased plasma LDL, increased GLP-1 and FGF21 levels, decreased adiposity, and hyperplasia of pancreatic α-cells in mouse models [6,[14][15][16]. The disruption of GCGR by antagonism or gene knockout in animal models also causes dysregulation of other metabolic processes, including cholesterol absorption, fatty acid utilization, white adipose tissue browning, and bile acid metabolism [17][18][19][20]. In humans, patients with GCGR mutations develop a syndrome known as Mahvash disease, characterized by hypercalcemia, hyperglucagonemia, and α-cell hyperplasia [21][22][23][24].…”

An endocrine-hepato-muscular metabolic cycle links skeletal muscle atrophy and hyperglycemia in type 2 diabetes

“…Despite glucagon receptor not being expressed in skeletal muscle but with potent liver expression and signaling (Fig. S6), chronic glucagon levels promote lean tissue wasting 29 and glucagonoma patients are known to present with muscle weakness 68 . Given that liver Gpt/2 silencing prevented skeletal muscle wasting and hyperglycaemia with chronic glucagon treatment ( Fig.…”

“…Indeed, muscle GR activity is required for chronic glucocorticoid effects on muscle atrophy 24,25 , which results in raised blood levels of certain amino acids 26 . Given that raised amino acids can trigger pancreatic glucagon (GCG) secretion [26][27][28] , and chronic glucagon treatment can reduce lean body mass 29,30 , we sought to investigate the role of GCG in T2D atrophy.…”