Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis.
3T3-L1 Cells
Adipocytes
/ metabolism
Adipogenesis
/ genetics
Adipose Tissue
/ metabolism
Animals
Biological Transport
Cell Differentiation
DNA-Binding Proteins
/ genetics
Diet, High-Fat
/ adverse effects
Energy Metabolism
/ genetics
Fatty Acids
/ metabolism
Feedback, Physiological
Female
Gene Expression Regulation
Homeostasis
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Obesity
/ etiology
PPAR gamma
/ genetics
Signal Transduction
Transcription Factors
/ genetics
Arid5a
Ppar-γ
adipogenesis
cytokines
obesity
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
23 07 2019
23 07 2019
Historique:
pubmed:
11
7
2019
medline:
31
3
2020
entrez:
11
7
2019
Statut:
ppublish
Résumé
Immune cells infiltrate adipose tissues and provide a framework to regulate energy homeostasis. However, the precise underlying mechanisms and signaling by which the immune system regulates energy homeostasis in metabolic tissues remain poorly understood. Here, we show that the AT-rich interactive domain 5A (Arid5a), a cytokine-induced nucleic acid binding protein, is important for the maintenance of adipose tissue homeostasis. Long-term deficiency of Arid5a in mice results in adult-onset severe obesity. In contrast, transgenic mice overexpressing Arid5a are highly resistant to high-fat diet-induced obesity. Inhibition of Arid5a facilitates the in vitro differentiation of 3T3-L1 cells and fibroblasts to adipocytes, whereas its induction substantially inhibits their differentiation. Molecular studies reveal that Arid5a represses the transcription of peroxisome proliferator activated receptor gamma 2 (Ppar-γ2) due to which, in the absence of Arid5a, Ppar-γ2 is persistently expressed in fibroblasts. This phenomenon is accompanied by enhanced fatty acid uptake in Arid5a-deficient cells, which shifts metabolic homeostasis toward prolipid metabolism. Furthermore, we show that Arid5a and Ppar-γ2 are dynamically counterregulated by each other, hence maintaining adipogenic homeostasis. Thus, we show that Arid5a is an important negative regulator of energy metabolism and can be a potential target for metabolic disorders.
Identifiants
pubmed: 31289228
pii: 1906712116
doi: 10.1073/pnas.1906712116
pmc: PMC6660722
doi:
Substances chimiques
Arid5a protein, mouse
0
DNA-Binding Proteins
0
Fatty Acids
0
PPAR gamma
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15128-15133Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Nat Med. 2002 Jan;8(1):75-9
pubmed: 11786910
Cell Growth Differ. 2002 Mar;13(3):95-106
pubmed: 11959810
Biochem Biophys Res Commun. 2002 Apr 26;293(1):560-5
pubmed: 12054638
J Biol Chem. 2003 Jul 25;278(30):28181-92
pubmed: 12732648
J Clin Endocrinol Metab. 2003 Jul;88(7):3005-10
pubmed: 12843134
Shock. 2005 May;23(5):393-9
pubmed: 15834303
Cell. 2005 Dec 16;123(6):993-9
pubmed: 16360030
Diabetes. 2006 Apr;55(4):971-7
pubmed: 16567518
Diabetes. 2006 Oct;55(10):2688-97
pubmed: 17003332
Drug Saf. 2007;30(12):1127-42
pubmed: 18035865
PPAR Res. 2008;2008:627463
pubmed: 18604287
Respiration. 2009;77(3):311-9
pubmed: 18974632
Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E174-83
pubmed: 19417127
Nat Rev Drug Discov. 2010 Jun;9(6):465-82
pubmed: 20514071
Mol Biol Cell. 2011 Apr 15;22(8):1300-11
pubmed: 21346191
Nat Med. 2011 May;17(5):618-22
pubmed: 21532596
Cell Metab. 2012 Aug 8;16(2):153-66
pubmed: 22795476
Cytokine. 2013 Feb;61(2):353-5
pubmed: 23228348
Nat Commun. 2012;3:1300
pubmed: 23250430
Am J Physiol Endocrinol Metab. 2013 Mar 1;304(5):E466-77
pubmed: 23269411
Nat Med. 2013 May;19(5):557-66
pubmed: 23652116
Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9409-14
pubmed: 23676272
Cell Biosci. 2014 May 29;4:29
pubmed: 24904744
Rev Endocr Metab Disord. 2015 Mar;16(1):47-54
pubmed: 25526866
Trends Immunol. 2015 Feb;36(2):92-101
pubmed: 25616716
Am J Physiol Endocrinol Metab. 2015 Oct 15;309(8):E691-714
pubmed: 26330344
Int J Mol Sci. 2016 Jan 19;17(1):null
pubmed: 26797605
J Exp Med. 2016 Apr 4;213(4):605-19
pubmed: 27022145
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11543-11548
pubmed: 27671645
PPAR Res. 2016;2016:7403230
pubmed: 28115925
Nucleic Acids Res. 2017 Mar 17;45(5):2687-2703
pubmed: 28168301
Int Immunol. 2017 Feb 1;29(2):79-85
pubmed: 28379390
Eur J Immunol. 2018 Apr;48(4):593-604
pubmed: 29244194
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1214-E1220
pubmed: 29358370
Sci Signal. 2018 Oct 09;11(551):
pubmed: 30301788
Cell Rep. 2018 Oct 23;25(4):1002-1017.e4
pubmed: 30355480
Cell Metab. 2019 Apr 2;29(4):844-855.e3
pubmed: 30595477
Cell. 1994 Dec 30;79(7):1147-56
pubmed: 8001151
Nucleic Acids Res. 1996 May 1;24(9):1695-701
pubmed: 8649988