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Adipose Tissue: ILC2 Crank Up the Heat

2015; Cell Press; Volume: 21; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2015.01.015

1932-7420

Melanie Flach, Andreas Diefenbach,

Adipokines, Inflammation, and Metabolic Diseases

White-to-beige conversion of adipocytes is one of the most promising approaches to therapeutically target obesity; however, the signals driving this process had largely remained unclear. Recently, two publications, Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar in Nature and Lee et al., 2015Lee M.W. Odegaard J.I. Mukundan L. Qiu Y. Molofsky A.B. Nussbaum J.C. Yun K. Locksley R.M. Chawla A. Cell. 2015; 160: 74-87Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar in Cell, showed that group 2 innate lymphoid cells directly regulate adipocyte differentiation and drive the growth of beige fat. White-to-beige conversion of adipocytes is one of the most promising approaches to therapeutically target obesity; however, the signals driving this process had largely remained unclear. Recently, two publications, Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar in Nature and Lee et al., 2015Lee M.W. Odegaard J.I. Mukundan L. Qiu Y. Molofsky A.B. Nussbaum J.C. Yun K. Locksley R.M. Chawla A. Cell. 2015; 160: 74-87Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar in Cell, showed that group 2 innate lymphoid cells directly regulate adipocyte differentiation and drive the growth of beige fat. Over the last decades, obesity has become a growing problem in industrial countries. When it comes to fat tissue, thermogenic beige adipocytes are considered more healthy than white adipose tissue, since their heat production leads to catabolic programs in white adipose tissue (WAT) and overall decreased fat mass. It had previously been shown that immune cells and "beiging" of WAT are closely intertwined. Eosinophils present in white adipose tissue sustain alternatively activated macrophages (AAMs) (Nguyen et al., 2011Nguyen K.D. Qiu Y. Cui X. Goh Y.P. Mwangi J. David T. Mukundan L. Brombacher F. Locksley R.M. Chawla A. Nature. 2011; 480: 104-108Crossref PubMed Scopus (773) Google Scholar, Wu et al., 2011Wu D. Molofsky A.B. Liang H.E. Ricardo-Gonzalez R.R. Jouihan H.A. Bando J.K. Chawla A. Locksley R.M. Science. 2011; 332: 243-247Crossref PubMed Scopus (965) Google Scholar). In response to eosinophil-derived IL-4, AAMs produce norepinephrine, which stimulates beige adipocytes and leads to a beneficial caloric balance (Qiu et al., 2014Qiu Y. Nguyen K.D. Odegaard J.I. Cui X. Tian X. Locksley R.M. Palmiter R.D. Chawla A. Cell. 2014; 157: 1292-1308Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar). Group 2 innate lymphoid cells (ILC2) react to IL-33 stimulation with the production of copious amounts of the type 2 cytokines IL-5 and IL-13. They were initially identified in fat-associated lymphoid clusters (Moro et al., 2010Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. Furusawa J. Ohtani M. Fujii H. Koyasu S. Nature. 2010; 463: 540-544Crossref PubMed Scopus (1506) Google Scholar) and were recently shown to be critical for recruitment and maintenance of WAT-resident eosinophils (Molofsky et al., 2013Molofsky A.B. Nussbaum J.C. Liang H.E. Van Dyken S.J. Cheng L.E. Mohapatra A. Chawla A. Locksley R.M. J. Exp. Med. 2013; 210: 535-549Crossref PubMed Scopus (629) Google Scholar). However, it had remained unclear whether ILC2 contribute to the beiging of WAT only via the eosinophil axis or whether they would have eosinophil-independent functions. Two recent publications have now elegantly addressed the mechanisms by which ILC2 might contribute to the generation of beige adipocytes (Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar, Lee et al., 2015Lee M.W. Odegaard J.I. Mukundan L. Qiu Y. Molofsky A.B. Nussbaum J.C. Yun K. Locksley R.M. Chawla A. Cell. 2015; 160: 74-87Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar). Both reports show that administration of the ILC2 stimulant IL-33 resulted in increased numbers of ILC2 in WAT, concurrent with an increase in beige fat cells and oxygen consumption. In contrast, IL-33 administration had no effect on brown adipose tissue. Artis and colleagues further reported that IL-33-deficient animals gained more weight than controls and showed increased WAT (Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar). At the same time, ILC2 and beige adipocyte numbers were reduced in WAT of Il33−/− animals. Intriguingly, reconstituting alymphoid mice (i.e., Rag2−/− Il2rg−/−) with ILC2 alone was sufficient to promote beiging of WAT, demonstrating a central role for IL-33 and ILC2 in the regulation of adipose tissue growth. Taking a closer look at adipocytes, Chawla and colleagues observed increased proliferation of adipocyte progenitors after IL-33 administration and both adipocyte progenitor numbers and proliferation were reduced in the absence of IL-4 signaling (Lee et al., 2015Lee M.W. Odegaard J.I. Mukundan L. Qiu Y. Molofsky A.B. Nussbaum J.C. Yun K. Locksley R.M. Chawla A. Cell. 2015; 160: 74-87Abstract Full Text Full Text PDF PubMed Scopus (490) Google Scholar). Surprisingly, tissue-specific deletion of IL-4Rα showed that IL-4 acted directly on adipocyte progenitors, bypassing the AAM-norepinephrine axis. As a result of stimulation with IL-4, adipocyte progenitors upregulated genes associated with differentiation of beige adipocytes, such as Ucp1, Klhl13, Tnfrsf9, and Tmem26. In contrast, IL-4Rα signaling was dispensable in differentiated adipocytes. Intriguingly, IL-4Rα does not only convey IL-4 signaling, but also binds IL-13, and both IL-4 and IL-13 led to proliferation of adipocyte progenitors upon administration in vivo. Even in the absence of IL-4-producing eosinophils, the authors detected substantial proliferation of adipocyte progenitors, suggesting that ILC2-derived IL-13 might act directly on adipocyte progenitors and could function synergistically with eosinophil-derived IL-4 to promote beige adipocyte development. However, the relative contribution of IL-4 and IL-13 remains to be shown. In order to determine how ILC2 contribute to beiging of WAT, Brestoff et al. compared obesity-associated genes expressed by ILC2, but not ILC3 (Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar). They discovered that proprotein convertase subtilisin/kexin type 1 (Pcsk1) as well as its target proenkephalin A (Penk) were highly expressed in ILC2. One product of Penk processing is the peptide methionine-enkephalin (MetEnk), of which the authors subsequently showed that it was produced by ILC2 and increased after IL-33 stimulation. Treatment of animals with MetEnk resulted in an increase of the beige adipocyte marker UCP1 in WAT as well as elevated oxygen consumption. Intriguingly, this phenotype is very likely independent of IL-4 and IL-13, since neither cytokine expression was changed upon MetEnk administration. However, Artis and colleagues found that one of the receptors for MetEnk, δ1 opioid receptor (Oprd1), was highly expressed in inguinal WAT (Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar). These data suggest that ILC2 can directly promote conversion of WAT into beige adipocytes by secreting MetEnk, which is sensed by δ1 opioid receptor on WAT and induces genes that promote beiging. However, studies using Oprd1 mutant animals will be needed to determine the role of MetEnk production by ILC2 in WAT beiging. While ILC2 were known to be present in mouse WAT, it had been less clear whether this would be applicable to humans. Brestoff et al. showed that ILC2 constitute a substantial fraction of lineage marker negative cells in adipose tissue of lean human donors (Brestoff et al., 2014Brestoff J.R. Kim B.S. Saenz S.A. Stine R.R. Monticelli L.A. Sonnenberg G.F. Thome J.J. Farber D.L. Lutfy K. Seale P. Artis D. Nature. 2014; (Published online December 22, 2014)https://doi.org/10.1038/nature14115Crossref PubMed Scopus (659) Google Scholar). Interestingly, fat tissue from obese patients as well as from mice fed with a high fat diet contained substantially fewer ILC2, although IL-33 expression is increased in adipose tissue of obese humans (Zeyda et al., 2013Zeyda M. Wernly B. Demyanets S. Kaun C. Hämmerle M. Hantusch B. Schranz M. Neuhofer A. Itariu B.K. Keck M. et al.Int. J. Obes. (Lond.). 2013; 37: 658-665Crossref PubMed Scopus (114) Google Scholar). One possible explanation for these contradictory findings might be that IL-33 sensing by ILC2 is dysregulated in the setting of adiposity. Taken together, an exciting insight into the role of innate immune system components (i.e., ILC2) in lipid metabolism is emerging. Although both reports identified different mechanisms as to how ILC2 control the beiging of WAT, it is well conceivable that these pathways synergize in the generation of beige adipocytes (Figure 1). Although it had previously been shown that eosinophils and AAM contribute to beiging, the groups of Artis and Chawla now demonstrate that ILC2 can directly regulate adipocyte development and differentiation, thus rendering them a promising target for future treatment of obesity. While both studies are largely promoting the same view, there are some small differences that need to be clarified in the future. In contrast to Lee et al., Artis and colleagues observed that administration of IL-33 to Il4ra−/− animals resulted in increased numbers of UCP1+ adipocytes, suggesting a direct role of IL-33 independent of IL-4 signaling. Several lines of inquiry will need to be pursued to better understand how ILC2 act on adipocytes. For example, it will be interesting to determine the relative contribution of IL-4, IL-13, and MetEnk to the beiging of WAT. From the above discussed publications, it remained unclear as to whether both pathways act on the same cells or whether there are multiple layers of regulation for the beiging of fat. Human white adipose tissue adipocytes were shown to produce IL-33, which can be increased by treatment with pro-inflammatory stimuli such as TNF (Wood et al., 2009Wood I.S. Wang B. Trayhurn P. Biochem. Biophys. Res. Commun. 2009; 384: 105-109Crossref PubMed Scopus (154) Google Scholar). However, it remains to be shown whether adipocytes themselves are the main source of IL-33 and how ILC2 affect this endogenous feedback mechanism. Lastly, it will be exciting to find how these pathways can be employed in order to increase IL-33 levels in vivo and pave new roads on the way to novel treatments of obesity. The A.D. lab is funded by grants from the European Research Council and the German Research Council (DFG).