Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.
Adipocytes
/ metabolism
Adipose Tissue, Brown
/ metabolism
Animals
COS Cells
Cells, Cultured
Chlorocebus aethiops
Cold Temperature
Constitutive Androstane Receptor
/ metabolism
Dietary Fats
/ pharmacology
Humans
Lipolysis
Mice, Inbred C57BL
Phenotype
Receptors, G-Protein-Coupled
/ genetics
Signal Transduction
Sympathetic Nervous System
/ metabolism
Thermogenesis
Transcription, Genetic
G protein-coupled receptor
GPCR
GPR3
adrenergic receptor
brown adipose tissue
constitutively active
energy expenditure
lipolysis
thermogenesis
transcription
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
24 06 2021
24 06 2021
Historique:
received:
21
02
2020
revised:
10
02
2021
accepted:
23
04
2021
pubmed:
29
5
2021
medline:
6
1
2022
entrez:
28
5
2021
Statut:
ppublish
Résumé
Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.
Identifiants
pubmed: 34048700
pii: S0092-8674(21)00572-9
doi: 10.1016/j.cell.2021.04.037
pmc: PMC8238500
pii:
doi:
Substances chimiques
Constitutive Androstane Receptor
0
Dietary Fats
0
GPR3 protein, human
0
GPR3 protein, mouse
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3502-3518.e33Subventions
Organisme : Medical Research Council
ID : MC_U105185859
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK118150
Pays : United States
Organisme : Wellcome Trust
ID : 212313/Z/18/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests O.S.J., Jakob Bondo Hansen, D.P.C., T.W.S., and Z.G.-H. work or have worked, in some capacity, for Embark Biotech ApS, a company developing therapeutics for the treatment of diabetes and obesity. All other authors declare no competing interests associated with this manuscript.
Références
Nat Chem Biol. 2013 Dec;9(12):785-7
pubmed: 24096302
Nature. 2019 Jan;565(7738):180-185
pubmed: 30568302
PLoS One. 2017 Sep 28;12(9):e0185624
pubmed: 28957413
Biochem J. 1995 Aug 1;309 ( Pt 3):837-43
pubmed: 7639700
Nat Commun. 2013;4:1769
pubmed: 23612310
Cell Rep. 2019 Sep 3;28(10):2567-2580.e6
pubmed: 31484069
Nature. 2014 Dec 18;516(7531):395-9
pubmed: 25317558
Nature. 2018 Aug;560(7716):102-106
pubmed: 30022159
Mol Metab. 2015 Nov 11;5(1):19-33
pubmed: 26844204
Circ Res. 2016 Jan 8;118(1):173-82
pubmed: 26837747
Nat Commun. 2015 Mar 10;6:6356
pubmed: 25754609
Science. 2002 Aug 2;297(5582):843-5
pubmed: 12161655
Diabetes. 2012 Aug;61(8):1986-93
pubmed: 22688341
Cell Metab. 2010 Apr 7;11(4):311-9
pubmed: 20374963
Mol Pharmacol. 2005 May;67(5):1414-25
pubmed: 15687224
J Biol Chem. 2016 Jan 8;291(2):508-20
pubmed: 26582202
Cell Metab. 2012 Mar 7;15(3):279-91
pubmed: 22405066
Cell Metab. 2015 Nov 3;22(5):851-60
pubmed: 26411340
Cell Metab. 2013 May 7;17(5):798-805
pubmed: 23663743
Am J Hum Genet. 2013 Dec 5;93(6):1072-86
pubmed: 24290377
Genes Dev. 2015 Feb 1;29(3):298-307
pubmed: 25644604
J Clin Invest. 2015 Feb;125(2):478-86
pubmed: 25642708
J Biol Chem. 2007 Apr 6;282(14):10576-84
pubmed: 17283075
Genome Biol. 2014;15(12):550
pubmed: 25516281
Mol Metab. 2019 Sep;27:11-21
pubmed: 31279640
Cell Metab. 2017 Nov 7;26(5):753-763.e7
pubmed: 28988821
Cell. 2012 Jul 20;150(2):366-76
pubmed: 22796012
Cell Metab. 2018 Jul 03;28(1):159-174.e11
pubmed: 29861389
Front Endocrinol (Lausanne). 2012 Jan 03;2:102
pubmed: 22654837
Cell Rep. 2016 Aug 23;16(8):2243-2258
pubmed: 27524617
Int J Obes (Lond). 2010 Oct;34 Suppl 1:S36-42
pubmed: 20935665
Exp Physiol. 2003 Jan;88(1):141-8
pubmed: 12525862
Cell Metab. 2013 May 7;17(5):638-43
pubmed: 23583169
Cell Rep. 2015 Dec 1;13(9):2000-13
pubmed: 26628366
Nat Commun. 2016 Mar 09;7:10895
pubmed: 26955961
Cell. 2014 Jul 3;158(1):69-83
pubmed: 24995979
Front Physiol. 2019 Jan 17;9:1931
pubmed: 30705635
Physiol Rev. 2004 Jan;84(1):277-359
pubmed: 14715917
J Clin Invest. 2013 Aug;123(8):3395-403
pubmed: 23867626
Nat Med. 2013 Oct;19(10):1252-63
pubmed: 24100998
J Biol Chem. 2012 Jul 20;287(30):25038-48
pubmed: 22685301
Biochem J. 1985 May 15;228(1):103-10
pubmed: 3890836
J Biol Chem. 2006 Dec 29;281(52):40236-41
pubmed: 17074755
Cell Rep. 2013 Dec 12;5(5):1196-203
pubmed: 24290753
J Exp Biol. 2018 Mar 7;221(Pt Suppl 1):
pubmed: 29514884
J Clin Invest. 2004 Oct;114(8):1158-64
pubmed: 15489963
Nature. 2000 Apr 6;404(6778):652-60
pubmed: 10766252
J Physiol. 1949 Aug;109(1-2):1-9
pubmed: 15394301
FASEB J. 2001 Sep;15(11):2048-50
pubmed: 11511509
Naunyn Schmiedebergs Arch Pharmacol. 2002 Nov;366(5):381-416
pubmed: 12382069
Nat Med. 2011 Feb;17(2):200-5
pubmed: 21258337
Physiol Rev. 2005 Oct;85(4):1159-204
pubmed: 16183910
Cell Metab. 2016 Jun 14;23(6):1200-1206
pubmed: 27238638
Cell. 2019 Jun 13;177(7):1933-1947.e25
pubmed: 31160049
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Cell Metab. 2020 Aug 4;32(2):287-300.e7
pubmed: 32755608
Methods Mol Biol. 2017;1566:77-85
pubmed: 28244042
J Neurosci Res. 2009 May 1;87(6):1329-33
pubmed: 19025769
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Adipocyte. 2015 Nov 20;5(2):175-85
pubmed: 27386153
Cell. 2015 Oct 22;163(3):643-55
pubmed: 26496606
Am J Physiol Endocrinol Metab. 2019 Mar 1;316(3):E487-E503
pubmed: 30576247
Trends Pharmacol Sci. 1993 Aug;14(8):303-7
pubmed: 8249148
Nat Cell Biol. 2013 Jun;15(6):659-67
pubmed: 23624403
Cell Metab. 2015 Jan 6;21(1):33-8
pubmed: 25565203
J Pharmacol Exp Ther. 2017 Dec;363(3):367-376
pubmed: 28928121
Biochim Biophys Acta. 2007 Apr;1768(4):794-807
pubmed: 17188232
Sci Rep. 2015 Oct 12;5:14953
pubmed: 26455425
Cell. 2018 Nov 29;175(6):1561-1574.e12
pubmed: 30449620
J Clin Endocrinol Metab. 2018 Feb 1;103(2):710-721
pubmed: 29121255
J Biol Methods. 2016 Jul 16;3(3):e48
pubmed: 31453213
Cell Metab. 2019 Apr 2;29(4):901-916.e8
pubmed: 30581121
Diabetes. 2005 Nov;54(11):3190-7
pubmed: 16249444
Nucleic Acids Res. 2015 Mar 31;43(6):e40
pubmed: 25564527
Drug Metab Rev. 2018 Feb;50(1):74-93
pubmed: 29390908
J Lipid Res. 2015 Jan;56(1):51-9
pubmed: 25351615
Nat Med. 2015 Jul;21(7):760-8
pubmed: 26076036
Nat Rev Endocrinol. 2017 Jan;13(1):26-35
pubmed: 27616452
Mol Metab. 2019 Sep;27:83-91
pubmed: 31272886
Obesity (Silver Spring). 2015 Jul;23(7):1450-9
pubmed: 26053335
Mol Metab. 2016 Oct 31;6(1):148-158
pubmed: 28123945
Mol Metab. 2019 Oct;28:14-25
pubmed: 31451430
Cell. 2014 Jan 16;156(1-2):20-44
pubmed: 24439368
Mol Metab. 2019 Apr;22:37-48
pubmed: 30772257