Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity?
G protein-coupled receptor (GPCR)
energy balance
glucagon-receptor (GCGR)
obesity
weight loss
Journal
Frontiers in endocrinology
ISSN: 1664-2392
Titre abrégé: Front Endocrinol (Lausanne)
Pays: Switzerland
ID NLM: 101555782
Informations de publication
Date de publication:
2022
2022
Historique:
received:
02
02
2022
accepted:
07
03
2022
entrez:
13
5
2022
pubmed:
14
5
2022
medline:
18
5
2022
Statut:
epublish
Résumé
A major challenge of obesity therapy is to sustain clinically relevant weight loss over time. Achieving this goal likely requires both reducing daily caloric intake and increasing caloric expenditure. Over the past decade, advances in pharmaceutical engineering of ligands targeting G protein-coupled receptors have led to the development of highly effective anorectic agents. These include mono-agonists of the GLP-1R and dual GIPR/GLP-1R co-agonists that have demonstrated substantial weight loss in experimental models and in humans. By contrast, currently, there are no medicines available that effectively augment metabolic rate to promote weight loss. Here, we present evidence indicating that activation of the GCGR may provide a solution to this unmet therapeutic need. In adult humans, GCGR agonism increases energy expenditure to a magnitude sufficient for inducing a negative energy balance. In preclinical studies, the glucagon-GCGR system affects key metabolically relevant organs (including the liver and white and brown adipose tissue) to boost whole-body thermogenic capacity and protect from obesity. Further, activation of the GCGR has been shown to augment both the magnitude and duration of weight loss that is achieved by either selective GLP-1R or dual GIPR/GLP-1R agonism in rodents. Based on the accumulation of such findings, we propose that the thermogenic activity of GCGR agonism will also complement other anti-obesity agents that lower body weight by suppressing appetite.
Identifiants
pubmed: 35547006
doi: 10.3389/fendo.2022.868037
pmc: PMC9081793
doi:
Substances chimiques
Glucagon-Like Peptide-1 Receptor
0
Receptors, Glucagon
0
Glucagon
9007-92-5
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
868037Informations de copyright
Copyright © 2022 Conceição-Furber, Coskun, Sloop and Samms.
Déclaration de conflit d'intérêts
All authors are current or past employees of Eli Lilly and Company.
Références
Nat Rev Endocrinol. 2019 May;15(5):288-298
pubmed: 30814686
J Clin Endocrinol Metab. 2015 Feb;100(2):342-62
pubmed: 25590212
Biochem Biophys Res Commun. 2002 Jan 18;290(2):839-43
pubmed: 11785978
Proc Soc Exp Biol Med. 1974 Mar;145(3):912-7
pubmed: 4818607
Pharmacol Rev. 2018 Oct;70(4):712-746
pubmed: 30087160
Am J Physiol. 1987 Jan;252(1 Pt 2):R160-5
pubmed: 3028165
Endocr Rev. 2019 Oct 1;40(5):1367-1393
pubmed: 31098621
Int J Obes (Lond). 2015 Aug;39(8):1188-96
pubmed: 25896063
Nutr Metab Cardiovasc Dis. 2020 Apr 12;30(4):616-624
pubmed: 32127340
Jpn J Physiol. 1983;33(3):367-76
pubmed: 6632371
N Engl J Med. 2021 Aug 5;385(6):503-515
pubmed: 34170647
Am J Physiol. 1983 Jun;244(6):R758-63
pubmed: 6859289
Clin Diabetes. 2020 Jan;38(1):10-38
pubmed: 31975748
F1000Res. 2018 Jul 9;7:
pubmed: 30026913
Obesity (Silver Spring). 2021 Apr;29 Suppl 1:S31-S38
pubmed: 33759394
Int J Mol Sci. 2019 Oct 30;20(21):
pubmed: 31671603
Nat Med. 2015 Jan;21(1):27-36
pubmed: 25485909
Cell Metab. 2019 Jan 8;29(1):27-37
pubmed: 30503034
JCI Insight. 2021 Feb 22;6(4):
pubmed: 33411693
Mol Metab. 2021 Sep;51:101237
pubmed: 33878401
Clin Med (Lond). 2014 Jun;14(3):286-9
pubmed: 24889574
Cell Metab. 2010 Apr 7;11(4):268-72
pubmed: 20374959
N Engl J Med. 2019 Dec 19;381(25):2440-2450
pubmed: 31851800
Br J Pharmacol Chemother. 1967 Nov;31(3):568-77
pubmed: 4295637
J Appl Physiol. 1957 Nov;11(3):419-21
pubmed: 13480952
Trends Endocrinol Metab. 2019 Aug;30(8):491-504
pubmed: 31248786
Endocrinology. 2014 Sep;155(9):3484-92
pubmed: 24949663
Nature. 2006 Jan 26;439(7075):484-9
pubmed: 16400329
Mol Cell Endocrinol. 1994 Nov;105(2):131-7
pubmed: 7859919
J Clin Invest. 2015 Feb;125(2):478-86
pubmed: 25642708
Diabetes Obes Metab. 2016 Jan;18(1):72-81
pubmed: 26434748
Lancet. 2018 Jun 30;391(10140):2607-2618
pubmed: 29945727
Horm Metab Res. 1983 Sep;15(9):429-32
pubmed: 6642413
Nat Rev Drug Discov. 2022 Mar;21(3):201-223
pubmed: 34815532
Diabetes Care. 2021 Jan;44(Suppl 1):S100-S110
pubmed: 33298419
Nat Rev Endocrinol. 2018 Jan;14(1):12-24
pubmed: 29027993
Compr Physiol. 2014 Jan;4(1):177-97
pubmed: 24692138
Int J Environ Res Public Health. 2017 Apr 19;14(4):
pubmed: 28422077
Cell Metab. 2015 May 5;21(5):731-8
pubmed: 25955208
J Clin Invest. 2004 Jun;113(11):1571-81
pubmed: 15173883
Nature. 2019 Aug;572(7771):614-619
pubmed: 31435015
Diabetes Obes Metab. 2016 Dec;18(12):1176-1190
pubmed: 27377054
Diabetologia. 2011 Feb;54(2):237-44
pubmed: 20953861
J Clin Endocrinol Metab. 1987 May;64(5):896-901
pubmed: 2881943
Obesity (Silver Spring). 2016 Aug;24(8):1607-8
pubmed: 27460708
Obesity (Silver Spring). 2016 Nov;24(11):2289-2295
pubmed: 27804272
Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R581-600
pubmed: 21677272
Physiol Rev. 2004 Jan;84(1):277-359
pubmed: 14715917
Diabetologia. 1994 Oct;37(10):985-93
pubmed: 7851693
Drug Des Devel Ther. 2015 Mar 30;9:1867-75
pubmed: 25848222
Nat Med. 2021 Jan;27(1):58-65
pubmed: 33398160
J Biol Chem. 1971 Mar 25;246(6):1872-6
pubmed: 4993962
J Biol Chem. 1961 Apr;236:1023-7
pubmed: 13710494
J Clin Endocrinol Metab. 1987 Jan;64(1):106-10
pubmed: 3536980
Obesity (Silver Spring). 2019 May;27(5):691-699
pubmed: 31012296
EMBO J. 1991 Jul;10(7):1635-41
pubmed: 1646711
Obesity (Silver Spring). 2021 Jun;29(6):1003-1013
pubmed: 34029448
N Engl J Med. 1961 May 4;264:893-7
pubmed: 13734109
Diabetes. 2004 Dec;53(12):3267-73
pubmed: 15561959
J Biol Chem. 1966 Feb 25;241(4):814-21
pubmed: 4285845
Metabolism. 1994 Aug;43(8):1000-5
pubmed: 8052138
J Health Econ. 2012 Jan;31(1):219-30
pubmed: 22094013
Diabetologia. 2013 Mar;56(3):588-97
pubmed: 23262585
Cell Metab. 2020 Apr 7;31(4):679-698
pubmed: 32187525
Horm Metab Res. 1980 Sep;12(9):430-3
pubmed: 7429415
J Biol Chem. 2020 Feb 14;295(7):1926-1942
pubmed: 31914415
Trends Endocrinol Metab. 2018 Mar;29(3):191-200
pubmed: 29366777
Nat Med. 2011 Feb;17(2):200-5
pubmed: 21258337
Clin Obes. 2021 Apr;11(2):e12433
pubmed: 33475251
Nat Rev Endocrinol. 2010 Dec;6(12):689-97
pubmed: 20957001
Cell Metab. 2014 Oct 7;20(4):670-7
pubmed: 25130400
Diabetes. 2009 Oct;58(10):2258-66
pubmed: 19602537
Diabetes. 2013 Apr;62(4):1131-8
pubmed: 23248172
Cell Metab. 2022 Jan 4;34(1):59-74.e10
pubmed: 34932984
Diabetes. 1987 Mar;36(3):382-9
pubmed: 2879758
Nat Rev Genet. 2022 Feb;23(2):120-133
pubmed: 34556834
FEBS Lett. 2007 Nov 13;581(27):5191-8
pubmed: 17950284
Mol Metab. 2019 Dec;30:72-130
pubmed: 31767182
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1438-43
pubmed: 12552113
Cell. 2012 Oct 12;151(2):400-13
pubmed: 23063128
Cell Metab. 2012 Jan 4;15(1):19-24
pubmed: 22225873
Am J Clin Nutr. 2012 Apr;95(4):989-94
pubmed: 22434603
Mol Metab. 2021 Apr;46:101178
pubmed: 33545391
Gene. 1994 Mar 25;140(2):203-9
pubmed: 8144028
Science. 1993 Mar 12;259(5101):1614-6
pubmed: 8384375
Mol Pharmacol. 2003 Jun;63(6):1256-72
pubmed: 12761335
Nat Chem Biol. 2009 Oct;5(10):749-57
pubmed: 19597507
FASEB J. 2019 Apr;33(4):4824-4835
pubmed: 30615494
Obesity (Silver Spring). 2016 Aug;24(8):1612-9
pubmed: 27136388
Int J Obes Relat Metab Disord. 2000 Mar;24(3):288-98
pubmed: 10757621
Nature. 1957 Nov 23;180(4595):1124
pubmed: 13483624
Diabetes Obes Metab. 2019 Jun;21(6):1357-1364
pubmed: 30740846
Genes Dev. 2013 Feb 1;27(3):234-50
pubmed: 23388824
Endocrinology. 2020 Jan 1;161(1):
pubmed: 31673703
N Engl J Med. 1995 Mar 9;332(10):621-8
pubmed: 7632212
Cancer Causes Control. 2017 Mar;28(3):247-258
pubmed: 28210884
Nature. 2008 Aug 21;454(7207):961-7
pubmed: 18719582
Nat Rev Drug Discov. 2016 Sep;15(9):639-660
pubmed: 27256476
Diabetes. 2013 May;62(5):1453-63
pubmed: 23305646
Lancet. 1975 May 3;1(7914):1036-2
pubmed: 48709
Diabetes. 2018 Sep;67(9):1773-1782
pubmed: 29925501
Pharmacoeconomics. 2015 Jul;33(7):673-89
pubmed: 25471927
Cell. 2014 Jan 16;156(1-2):20-44
pubmed: 24439368
J Physiol. 1966 Nov;187(2):271-83
pubmed: 4291385
Genes Dev. 2012 Feb 1;26(3):271-81
pubmed: 22302939
Nat Med. 2020 Apr;26(4):485-497
pubmed: 32127716
Mol Metab. 2019 Apr;22:37-48
pubmed: 30772257
Expert Opin Investig Drugs. 2017 Dec;26(12):1373-1389
pubmed: 29052441