PPARγ and PPARα synergize to induce robust browning of white fat in vivo.
Adipocytes, Brown
/ metabolism
Adipocytes, White
/ metabolism
Adipose Tissue, Brown
/ metabolism
Adipose Tissue, White
/ metabolism
Animals
Energy Metabolism
Male
Mice
Mice, Inbred C57BL
PPAR alpha
/ genetics
PPAR gamma
/ genetics
Thermogenesis
/ genetics
Transcription Factors
/ metabolism
Uncoupling Protein 1
/ metabolism
Beige adipocytes
Brown adipocytes
FGF21
PPAR
Thermogenesis
UCP1
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
28
10
2019
revised:
12
02
2020
accepted:
12
02
2020
pubmed:
6
4
2020
medline:
3
7
2021
entrez:
6
4
2020
Statut:
ppublish
Résumé
Peroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat. A selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice. All dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. PPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21.
Identifiants
pubmed: 32248079
pii: S2212-8778(20)30036-3
doi: 10.1016/j.molmet.2020.02.007
pmc: PMC7132097
pii:
doi:
Substances chimiques
PPAR alpha
0
PPAR gamma
0
Transcription Factors
0
Uncoupling Protein 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100964Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL144472
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
Références
Diabetes. 2009 Jul;58(7):1526-31
pubmed: 19401428
Biochimie. 2017 Mar;134:127-137
pubmed: 28109720
PPAR Res. 2013;2013:305347
pubmed: 24285952
Eur J Pharmacol. 1999 Jan 8;364(2-3):211-9
pubmed: 9932726
Front Endocrinol (Lausanne). 2015 Nov 19;6:174
pubmed: 26635723
Diabetologia. 2005 Sep;48(9):1716-25
pubmed: 16001233
Cell. 2012 Aug 3;150(3):620-32
pubmed: 22863012
Diabetes. 2000 May;49(5):759-67
pubmed: 10905484
Cell Rep. 2013 Dec 12;5(5):1196-203
pubmed: 24290753
Cell Metab. 2015 Jan 6;21(1):33-8
pubmed: 25565203
EMBO Rep. 2004 Feb;5(2):142-7
pubmed: 14755307
Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1327-35
pubmed: 19211718
Cell Metab. 2012 Mar 7;15(3):395-404
pubmed: 22405074
PLoS One. 2018 Jan 19;13(1):e0191365
pubmed: 29351550
Bioorg Med Chem Lett. 2009 May 1;19(9):2468-73
pubmed: 19349176
Br J Pharmacol. 2003 Oct;140(3):527-37
pubmed: 12970088
J Biol Chem. 2001 Jan 12;276(2):1486-93
pubmed: 11050084
Endocr Rev. 1999 Oct;20(5):649-88
pubmed: 10529898
Genes Dev. 2012 Feb 15;26(4):312-24
pubmed: 22302876
Structure. 2001 Aug;9(8):699-706
pubmed: 11587644
Cell Metab. 2007 Jun;5(6):415-25
pubmed: 17550777
J Biol Chem. 2011 Dec 16;286(50):43112-22
pubmed: 22033933
Cell. 2012 Jul 20;150(2):366-76
pubmed: 22796012
Diabetes. 2004 Feb;53 Suppl 1:S43-50
pubmed: 14749265
Diabetes. 2000 Dec;49(12):2108-15
pubmed: 11118014
Diab Vasc Dis Res. 2007 Sep;4(3):194-203
pubmed: 17907109
J Clin Invest. 2004 Nov;114(9):1281-9
pubmed: 15520860
Am J Physiol Endocrinol Metab. 2016 Dec 1;311(6):E901-E910
pubmed: 27780820
Eur J Pharmacol. 2004 Jul 8;495(1):17-26
pubmed: 15219816
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Jan;1864(1):13-19
pubmed: 29763732
Physiol Rev. 2004 Jan;84(1):277-359
pubmed: 14715917
Endocrinology. 2008 May;149(5):2121-30
pubmed: 18218698
Cell Rep. 2019 Apr 2;27(1):213-225.e5
pubmed: 30943403
Endocrinology. 2008 Dec;149(12):6018-27
pubmed: 18687777
Diabetes. 2015 Jul;64(7):2369-75
pubmed: 26050669
N Engl J Med. 2009 Apr 9;360(15):1500-8
pubmed: 19357405
Endocrinology. 2004 Aug;145(8):3925-34
pubmed: 15131020
Br J Pharmacol. 2006 Jul;148(5):610-8
pubmed: 16751799
Cell Metab. 2014 Oct 7;20(4):670-7
pubmed: 25130400
J Biol Chem. 2010 Mar 5;285(10):7153-64
pubmed: 20028987
Mol Metab. 2016 Mar 18;5(5):352-365
pubmed: 27110487
Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E287-96
pubmed: 18492776
Pharmacol Res Perspect. 2015 Jun;3(3):e00136
pubmed: 26171220
J Clin Invest. 2011 Jan;121(1):96-105
pubmed: 21123942
Cell Metab. 2007 Jun;5(6):426-37
pubmed: 17550778
Stem Cells. 2009 Nov;27(11):2753-60
pubmed: 19697348
Mol Endocrinol. 2015 Jan;29(1):130-9
pubmed: 25389910
J Med Chem. 2005 Mar 24;48(6):2248-50
pubmed: 15771468
Mol Cell Endocrinol. 2015 Feb 15;402:86-94
pubmed: 25576856
Mol Metab. 2018 Jan;7:161-170
pubmed: 29122558
Mol Cell Biol. 2009 Sep;29(17):4714-28
pubmed: 19564408
Diabetes. 2007 Jul;56(7):1751-60
pubmed: 17456854
Cell Metab. 2016 Dec 13;24(6):835-847
pubmed: 27974179
Diabetologia. 2002 Sep;45(9):1201-10
pubmed: 12242452
PLoS One. 2011;6(11):e26989
pubmed: 22087241
N Engl J Med. 2009 Apr 9;360(15):1509-17
pubmed: 19357406
Cell Metab. 2014 Apr 1;19(4):593-604
pubmed: 24703692
PPAR Res. 2010;2010:
pubmed: 20936127
Endocrinology. 2015 Jul;156(7):2470-81
pubmed: 25924103
J Cell Sci. 1992 Dec;103 ( Pt 4):931-42
pubmed: 1362571
J Biol Chem. 2017 Jun 2;292(22):9175-9190
pubmed: 28404815
Genes Dev. 2012 Feb 1;26(3):271-81
pubmed: 22302939
N Engl J Med. 2009 Apr 9;360(15):1518-25
pubmed: 19357407