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Habegger, K.M.* ; Stemmer, K. ; Cheng, C.* ; Müller, T.D. ; Heppner, K.M.* ; Ottaway, N.* ; Holland, J.* ; Hembree, J.L.* ; Smiley, D.* ; Gelfanov, V.* ; Krishna, R.* ; Arafat, A.M.* ; Konkar, A.* ; Belli, S.* ; Kapps, M.* ; Woods, S.C.* ; Hofmann, S.M. ; D'Alessio, D.* ; Pfluger, P.T. ; Perez-Tilve, D.* ; Seeley, R.J.* ; Konishi, M.* ; Itoh, N.* ; Kharitonenkov, A.* ; Spranger, J.* ; DiMarchi, R.D.* ; Tschöp, M.H.

Fibroblast growth factor 21 mediates specific glucagon actions.

Diabetes 62, 1453-1463 (2013)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Increases Energy-expenditure ; Ppar-alpha ; Insulin Sensitivity ; Body-weight ; Metabolism ; Mice ; Fgf21 ; Fibroblast-growth-factor-21 ; Pharmacology ; Degradation
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 62, Issue: 5, Pages: 1453-1463 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Experimental Genetics (IEG)
Institute of Diabetes and Regeneration Research (IDR)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502200-001
G-500690-001
G-502390-001
PubMed ID 23305646
DOI 10.2337/db12-1116
WOS ID WOS:000318128700024
Scopus ID 84876542381
Erfassungsdatum 2013-01-28
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