Fibroblast growth factor 21 mediates specific glucagon actions.

Abstract

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.

• Authors: Kirk M Habegger, Kerstin Stemmer, Christine Cheng, Timo D Müller, Kristy M Heppner, Nickki Ottaway, Jenna Holland, Jazzminn L Hembree, David Smiley, Vasily Gelfanov, Radha Krishna, Ayman M Arafat, Anish Konkar, Sara Belli, Martin Kapps, Stephen C Woods, Susanna M Hofmann, David D'Alessio, Paul T Pfluger, Diego Perez-Tilve, Randy J Seeley, Morichika Konishi, Nobuyujki Itoh, Alexei Kharitonenkov, Joachim Spranger, Richard D DiMarchi, Matthias H Tschöp
• Journal: Diabetes (Diabetes) Vol. 62 Issue 5 Pg. 1453-63 (May 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23305646 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Hypoglycemic Agents
• IUB288
• Peptides
• Receptors, Glucagon
• Recombinant Proteins
• fibroblast growth factor 21
• Fibroblast Growth Factors
• Glucagon

Topics

• Adult
• Animals
• Anti-Obesity Agents (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)
• Cells, Cultured
• Cross-Over Studies
• Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism)
• Double-Blind Method
• Female
• Fibroblast Growth Factors (blood, genetics, metabolism)
• Glucagon (agonists, metabolism, pharmacology)
• HEK293 Cells
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Hypoglycemic Agents (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)
• Insulin Resistance
• Male
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Molecular Targeted Therapy
• Obesity (blood, drug therapy, metabolism)
• Peptides (chemical synthesis, pharmacokinetics, physiology, therapeutic use)
• Rats
• Receptors, Glucagon (agonists, genetics, metabolism)
• Recombinant Proteins (agonists, metabolism)