Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

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 treatme...

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Main Authors:	Habegger, Kirk M., Stemmer, Kerstin, Cheng, Christine, Müller, Timo D., Heppner, Kristy M., Ottaway, Nickki, Holland, Jenna, Hembree, Jazzminn L., Smiley, David, Gelfanov, Vasily, Krishna, Radha, Arafat, Ayman M., Konkar, Anish, Belli, Sara, Kapps, Martin, Woods, Stephen C., Hofmann, Susanna M., D’Alessio, David, Pfluger, Paul T., Perez-Tilve, Diego, Seeley, Randy J., Konishi, Morichika, Itoh, Nobuyujki, Kharitonenkov, Alexei, Spranger, Joachim, DiMarchi, Richard D., Tschöp, Matthias H.
Format:	Online
Language:	English
Published:	American Diabetes Association 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636653/

id	pubmed-3636653
recordtype	oai_dc
spelling	pubmed-36366532014-05-01 Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions Habegger, Kirk M. Stemmer, Kerstin Cheng, Christine Müller, Timo D. Heppner, Kristy M. Ottaway, Nickki Holland, Jenna Hembree, Jazzminn L. Smiley, David Gelfanov, Vasily Krishna, Radha Arafat, Ayman M. Konkar, Anish Belli, Sara Kapps, Martin Woods, Stephen C. Hofmann, Susanna M. D’Alessio, David Pfluger, Paul T. Perez-Tilve, Diego Seeley, Randy J. Konishi, Morichika Itoh, Nobuyujki Kharitonenkov, Alexei Spranger, Joachim DiMarchi, Richard D. Tschöp, Matthias H. Original Research 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. American Diabetes Association 2013-05 2013-04-16 /pmc/articles/PMC3636653/ /pubmed/23305646 http://dx.doi.org/10.2337/db12-1116 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Habegger, Kirk M. Stemmer, Kerstin Cheng, Christine Müller, Timo D. Heppner, Kristy M. Ottaway, Nickki Holland, Jenna Hembree, Jazzminn L. Smiley, David Gelfanov, Vasily Krishna, Radha Arafat, Ayman M. Konkar, Anish Belli, Sara Kapps, Martin Woods, Stephen C. Hofmann, Susanna M. D’Alessio, David Pfluger, Paul T. Perez-Tilve, Diego Seeley, Randy J. Konishi, Morichika Itoh, Nobuyujki Kharitonenkov, Alexei Spranger, Joachim DiMarchi, Richard D. Tschöp, Matthias H.
spellingShingle	Habegger, Kirk M. Stemmer, Kerstin Cheng, Christine Müller, Timo D. Heppner, Kristy M. Ottaway, Nickki Holland, Jenna Hembree, Jazzminn L. Smiley, David Gelfanov, Vasily Krishna, Radha Arafat, Ayman M. Konkar, Anish Belli, Sara Kapps, Martin Woods, Stephen C. Hofmann, Susanna M. D’Alessio, David Pfluger, Paul T. Perez-Tilve, Diego Seeley, Randy J. Konishi, Morichika Itoh, Nobuyujki Kharitonenkov, Alexei Spranger, Joachim DiMarchi, Richard D. Tschöp, Matthias H. Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
author_facet	Habegger, Kirk M. Stemmer, Kerstin Cheng, Christine Müller, Timo D. Heppner, Kristy M. Ottaway, Nickki Holland, Jenna Hembree, Jazzminn L. Smiley, David Gelfanov, Vasily Krishna, Radha Arafat, Ayman M. Konkar, Anish Belli, Sara Kapps, Martin Woods, Stephen C. Hofmann, Susanna M. D’Alessio, David Pfluger, Paul T. Perez-Tilve, Diego Seeley, Randy J. Konishi, Morichika Itoh, Nobuyujki Kharitonenkov, Alexei Spranger, Joachim DiMarchi, Richard D. Tschöp, Matthias H.
author_sort	Habegger, Kirk M.
title	Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
title_short	Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
title_full	Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
title_fullStr	Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
title_full_unstemmed	Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
title_sort	fibroblast growth factor 21 mediates specific glucagon actions
description	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.
publisher	American Diabetes Association
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636653/
_version_	1611972857888243712

Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

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