title: 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.affiliation: Metabolic Disease Institute, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.forename: Christine
authors.initials: C
authors.lastname: Cheng
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Jazzminn L
authors.initials: JL
authors.lastname: Hembree
authors.forename: David
authors.initials: D
authors.lastname: Smiley
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.forename: Radha
authors.initials: R
authors.lastname: Krishna
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Arafat
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.forename: Sara
authors.initials: S
authors.lastname: Belli
authors.forename: Martin
authors.initials: M
authors.lastname: Kapps
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
authors.forename: David
authors.initials: D
authors.lastname: D'Alessio
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: Morichika
authors.initials: M
authors.lastname: Konishi
authors.forename: Nobuyujki
authors.initials: N
authors.lastname: Itoh
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000328:Adult; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000819:agonists / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000502:physiology / Q000627:therapeutic use; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; C581932:IUB288; D010455:Peptides; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon