Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation.
Adipocytes
/ metabolism
Adult
Animals
Body Weight
/ physiology
Cell Line
Diabetes Mellitus, Type 2
/ metabolism
Diet
/ methods
HEK293 Cells
Homeodomain Proteins
/ metabolism
Humans
Inflammation
/ metabolism
Macrophages
/ metabolism
Male
Metabolic Diseases
/ metabolism
Mice
Obesity
/ metabolism
RAW 264.7 Cells
THP-1 Cells
Thermogenesis
/ physiology
Transcription Factors
/ metabolism
Transcription, Genetic
/ physiology
Young Adult
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
11
11
2020
accepted:
04
08
2021
pubmed:
25
9
2021
medline:
13
10
2021
entrez:
24
9
2021
Statut:
ppublish
Résumé
Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.
Identifiants
pubmed: 34556885
doi: 10.1038/s41590-021-01023-y
pii: 10.1038/s41590-021-01023-y
doi:
Substances chimiques
Homeodomain Proteins
0
Irx3 protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1268-1279Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000).
pubmed: 10766252
doi: 10.1038/35007527
Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
pubmed: 22796012
pmcid: 3402601
doi: 10.1016/j.cell.2012.05.016
Wang, W. & Seale, P. Control of brown and beige fat development. Nat. Rev. Mol. Cell Biol. 17, 691–702 (2016).
pubmed: 27552974
pmcid: 5627770
doi: 10.1038/nrm.2016.96
Qiu, Y., Shan, B., Yang, L. & Liu, Y. Adipose tissue macrophage in immune regulation of metabolism. Sci. China Life Sci. 59, 1232–1240 (2016).
pubmed: 27837402
doi: 10.1007/s11427-016-0155-1
Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).
pubmed: 24100998
doi: 10.1038/nm.3361
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
pubmed: 24439368
pmcid: 3934003
doi: 10.1016/j.cell.2013.12.012
Mathis, D. Immunological goings-on in visceral adipose tissue. Cell Metab. 17, 851–859 (2013).
pubmed: 23747244
pmcid: 4264591
doi: 10.1016/j.cmet.2013.05.008
Mowers, J. et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1. Elife 2, e01119 (2013).
pubmed: 24368730
pmcid: 3869376
doi: 10.7554/eLife.01119
Sakamoto, T. et al. Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice. Am. J. Physiol. Endocrinol. Metab. 310, E676–E687 (2016).
pubmed: 26884382
doi: 10.1152/ajpendo.00028.2015
Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749 (2011).
pubmed: 21984069
pmcid: 3383854
doi: 10.1038/nri3071
Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).
pubmed: 17496892
doi: 10.1038/ng2048
Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).
pubmed: 17434869
pmcid: 2646098
doi: 10.1126/science.1141634
Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).
pubmed: 17658951
pmcid: 1934391
doi: 10.1371/journal.pgen.0030115
Fischer, J. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009).
pubmed: 19234441
doi: 10.1038/nature07848
Church, C. et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat. Genet. 42, 1086–1092 (2010).
pubmed: 21076408
pmcid: 3018646
doi: 10.1038/ng.713
Grunnet, L. G. et al. Regulation and function of FTO mRNA expression in human skeletal muscle and subcutaneous adipose tissue. Diabetes 58, 2402–2408 (2009).
pubmed: 19587359
pmcid: 2750213
doi: 10.2337/db09-0205
Kloting, N. et al. Inverse relationship between obesity and FTO gene expression in visceral adipose tissue in humans. Diabetologia 51, 641–647 (2008).
pubmed: 18251005
doi: 10.1007/s00125-008-0928-9
Wahlen, K., Sjolin, E. & Hoffstedt, J. The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis. J. Lipid Res. 49, 607–611 (2008).
pubmed: 18048838
doi: 10.1194/jlr.M700448-JLR200
Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014).
pubmed: 24646999
pmcid: 4113484
doi: 10.1038/nature13138
Kim, K. H., Rosen, A., Bruneau, B. G., Hui, C. C. & Backx, P. H. Iroquois homeodomain transcription factors in heart development and function. Circ. Res. 110, 1513–1524 (2012).
pubmed: 22628575
doi: 10.1161/CIRCRESAHA.112.265041
de Araujo, T. M. & Velloso, L. A. Hypothalamic IRX3: a new player in the development of obesity. Trends Endocrinol. Metab. 31, 368–377 (2020).
pubmed: 32035736
doi: 10.1016/j.tem.2020.01.002
Claussnitzer, M. et al. FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 373, 895–907 (2015).
pubmed: 26287746
pmcid: 4959911
doi: 10.1056/NEJMoa1502214
Zou, Y. et al. IRX3 promotes the browning of white adipocytes and its rare variants are associated with human obesity risk. EBioMedicine 24, 64–75 (2017).
pubmed: 28988979
pmcid: 5652024
doi: 10.1016/j.ebiom.2017.09.010
de Araujo, T. M. et al. The partial inhibition of hypothalamic IRX3 exacerbates obesity. EBioMedicine 39, 448–460 (2019).
pubmed: 30522931
doi: 10.1016/j.ebiom.2018.11.048
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
pubmed: 14715917
doi: 10.1152/physrev.00015.2003
Morrison, S. F., Madden, C. J. & Tupone, D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 19, 741–756 (2014).
pubmed: 24630813
pmcid: 4016184
doi: 10.1016/j.cmet.2014.02.007
Hoffmann, C., Leitz, M. R., Oberdorf-Maass, S., Lohse, M. J. & Klotz, K. N. Comparative pharmacology of human beta-adrenergic receptor subtypes–characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch. Pharmacol. 369, 151–159 (2004).
pubmed: 14730417
doi: 10.1007/s00210-003-0860-y
Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).
pubmed: 17313320
pmcid: 2885771
doi: 10.1146/annurev.nutr.27.061406.093734
Fredriksson, J. M. et al. Analysis of inhibition by H89 of UCP1 gene expression and thermogenesis indicates protein kinase A mediation of β
pubmed: 11336791
doi: 10.1016/S0167-4889(01)00070-2
Brito, N. A., Brito, M. N. & Bartness, T. J. Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1445–1452 (2008).
pubmed: 18321949
doi: 10.1152/ajpregu.00068.2008
Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).
pubmed: 24906148
pmcid: 4129510
doi: 10.1016/j.cell.2014.03.066
Goto, T. et al. Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine 77, 107–114 (2016).
pubmed: 26556104
doi: 10.1016/j.cyto.2015.11.001
Chung, K. J. et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat. Immunol. 18, 654–664 (2017).
pubmed: 28414311
pmcid: 5436941
doi: 10.1038/ni.3728
Huang, C. H. et al. UbiSite: incorporating two-layered machine learning method with substrate motifs to predict ubiquitin-conjugation site on lysines. BMC Syst. Biol. 10, 6 (2016).
pubmed: 26818456
pmcid: 4895383
doi: 10.1186/s12918-015-0246-z
Lu, Y. C., Yeh, W. C. & Ohashi, P. S. LPS/TLR4 signal transduction pathway. Cytokine 42, 145–151 (2008).
pubmed: 18304834
doi: 10.1016/j.cyto.2008.01.006
Lei, K. et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH
pubmed: 12052897
pmcid: 133923
doi: 10.1128/MCB.22.13.4929-4942.2002
Han, M. S. et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218–222 (2013).
pubmed: 23223452
doi: 10.1126/science.1227568
Wang, C. et al. GPS 5.0: an update on the prediction of kinase-specific phosphorylation sites in proteins. Genomics Proteomics Bioinformatics 18, 72–80 (2020).
pubmed: 32200042
pmcid: 7393560
doi: 10.1016/j.gpb.2020.01.001
Bilioni, A., Craig, G., Hill, C. & McNeill, H. Iroquois transcription factors recognize a unique motif to mediate transcriptional repression in vivo. Proc. Natl Acad. Sci. USA 102, 14671–14676 (2005).
pubmed: 16203991
pmcid: 1239941
doi: 10.1073/pnas.0502480102
Berger, M. F. et al. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133, 1266–1276 (2008).
pubmed: 18585359
pmcid: 2531161
doi: 10.1016/j.cell.2008.05.024
Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).
pubmed: 16932750
doi: 10.1038/nri1900
Villarino, A. V., Kanno, Y. & O’Shea, J. J. Mechanisms and consequences of Jak–STAT signaling in the immune system. Nat. Immunol. 18, 374–384 (2017).
pubmed: 28323260
doi: 10.1038/ni.3691
Hill, D. A. et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc. Natl Acad. Sci. USA 115, E5096–E5105 (2018).
pubmed: 29760084
pmcid: 5984532
doi: 10.1073/pnas.1802611115
Abram, C. L., Roberge, G. L., Hu, Y. & Lowell, C. A. Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J. Immunol. Methods 408, 89–100 (2014).
pubmed: 24857755
pmcid: 4105345
doi: 10.1016/j.jim.2014.05.009
Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443 (2004).
pubmed: 15507213
doi: 10.1016/j.cell.2004.10.010
Orthgiess, J. et al. Neurons exhibit Lyz2 promoter activity in vivo: implications for using LysM-Cre mice in myeloid cell research. Eur. J. Immunol. 46, 1529–1532 (2016).
pubmed: 27062494
doi: 10.1002/eji.201546108
Gomez-Skarmeta, J. L., Diez del Corral, R., de la Calle-Mustienes, E., Ferre-Marco, D. & Modolell, J. Araucan and caupolican, two members of the novel iroquois complex, encode homeoproteins that control proneural and vein-forming genes. Cell 85, 95–105 (1996).
pubmed: 8620542
doi: 10.1016/S0092-8674(00)81085-5
Creely, S. J. et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 292, E740–747 (2007).
pubmed: 17090751
doi: 10.1152/ajpendo.00302.2006
Lancaster, G. I. et al. Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab. 27, 1096–1110 e1095 (2018).
pubmed: 29681442
doi: 10.1016/j.cmet.2018.03.014
Zhi, X. et al. AdipoCount: a new software for automatic adipocyte counting. Front Physiol. 9, 85 (2018).
pubmed: 29515452
pmcid: 5826178
doi: 10.3389/fphys.2018.00085
Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).
pubmed: 24906148
pmcid: 4129510
doi: 10.1016/j.cell.2014.03.066
Shan, B. et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat. Immunol. 18, 519–529 (2017).
pubmed: 28346409
doi: 10.1038/ni.3709