Fibroblast growth factor 21 mediates specific glucagon actions

Area of Science:

• Endocrinology
• Metabolic research
• Pharmacology

Background:

• Glucagon is vital for glucose homeostasis, lipid metabolism, and weight regulation.
• Glucagon receptor (GcgR) agonists are emerging as therapeutics for obesity and diabetes.
• Understanding glucagon's precise metabolic roles is crucial for therapeutic development.

Purpose of the Study:

• To develop and utilize a novel GcgR agonist to investigate glucagon's in vivo actions.
• To elucidate the role of fibroblast growth factor 21 (FGF21) in mediating GcgR-dependent metabolic changes.

Main Methods:

• Administration of a novel GcgR agonist to wild-type and GcgR knockout mice.
• In vitro studies using primary hepatocytes.
• Analysis of hepatic gene expression and plasma metabolite levels.
• Studies in mice with genetic deletion of FGF21.
• Administration of natural glucagon to healthy human volunteers.

Main Results:

• Chronic GcgR agonism in mice led to hyperglycemia, reduced body fat, and lower plasma cholesterol.
• GcgR activation increased hepatic expression and circulating levels of FGF21 in mice.
• This FGF21 induction was dependent on GcgR presence.
• Glucagon injection increased plasma FGF21 in humans.
• GcgR activation failed to induce weight loss and lipid changes in FGF21-deficient mice.

Conclusions:

• Glucagon receptor signaling stimulates FGF21 production.
• FGF21 mediates key glucagon-induced effects on body weight and lipid metabolism.
• Glucagon influences glucose, energy, and lipid metabolism, in part, through FGF21-dependent pathways.