Cell Metabolism

Previews Adipose Tissue: ILC2 Crank Up the Heat Melanie Flach1 and Andreas Diefenbach1,*

1Research Centre of Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2015.01.015

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. (2014) in Nature and Lee et al. (2015) 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., 2011; Wu et al., 2011). In response to eosinophilderived IL-4, AAMs produce norepinephrine, which stimulates beige adipocytes and leads to a beneficial caloric balance (Qiu et al., 2014). 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., 2010) and were recently shown to be critical for recruitment and maintenance of WAT-resident eosinophils (Molofsky et al., 2013). 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., 2014; Lee et al., 2015). 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., 2014). 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., 2015). Surprisingly, tissue-specific deletion of IL-4Ra showed that IL-4 acted directly on adipocyte progenitors, bypassing the AAMnorepinephrine 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-4Ra signaling was dispensable in differentiated adipocytes. Intriguingly, IL-4Ra 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

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expressed by ILC2, but not ILC3 (Brestoff et al., 2014). 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, d1 opioid receptor (Oprd1), was highly expressed in inguinal WAT (Brestoff et al., 2014). These data suggest that ILC2 can directly promote conversion of WAT into beige adipocytes by secreting MetEnk, which is sensed by d1 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., 2014). 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., 2013). One possible explanation for these contradictory findings might be that IL-33 sensing

Cell Metabolism

Previews by ILC2 is dysregulated in the new roads on the way to IL-4 setting of adiposity. novel treatments of obesity. Eosinophil Taken together, an exciting insight into the role of innate ACKNOWLEDGMENTS Alternatively Activated IL-4 Macrophage immune system components IL-5 The A.D. lab is funded by grants (i.e., ILC2) in lipid metabolism from the European Research is emerging. Although both reIL-4Rα chain Council and the German Research ports identified different mechaCouncil (DFG). IL-13 nisms as to how ILC2 control the Norepinephrine beiging of WAT, it is well REFERENCES ILC2 conceivable that these pathAdipocyte Progenitor IL-33 IL-33 ways synergize in the generBrestoff, J.R., Kim, B.S., Saenz, S.A., Stine, R.R., Monticelli, L.A., ation of beige adipocytes MetEnk ? MetEnk ? Sonnenberg, G.F., Thome, J.J., (Figure 1). Although it had previFarber, D.L., Lutfy, K., Seale, P., ously been shown that eosinoand Artis, D. (2014). Nature. Published online December 22, 2014. phils and AAM contribute to http://dx.doi.org/10.1038/nabeiging, the groups of Artis ture14115. and Chawla now demonstrate Lee, M.W., Odegaard, J.I., Mukunthat ILC2 can directly regulate dan, L., Qiu, Y., Molofsky, A.B., adipocyte development and Nussbaum, J.C., Yun, K., LocksWhite Adipocyte Beige Adipocyte ley, R.M., and Chawla, A. (2015). differentiation, thus rendering Cell 160, 74–87. them a promising target for Figure 1. ILC2 Play a Central Role in Beiging of White Adipose future treatment of obesity. Molofsky, A.B., Nussbaum, J.C., Tissue Liang, H.E., Van Dyken, S.J., While both studies are largely ILC2 can regulate beiging of adipose tissue in multiple ways after being trigCheng, L.E., Mohapatra, A., gered by IL-33. On the one hand, they produce the type 2 cytokine IL-5, which promoting the same view, Chawla, A., and Locksley, R.M. in turn activates eosinophils and triggers IL-4 production. In response to IL-4, there are some small differ(2013). J. Exp. Med. 210, 535–549. alternatively activated macrophages produce norepinephrine that results in ences that need to be clarified beiging of adipose tissue. New data by Lee et al. demonstrate that eosinoMoro, K., Yamada, T., Tanabe, M., phil-derived IL-4 as well as ILC2-derived IL-13 (receptor complexes of both in the future. In contrast to Takeuchi, T., Ikawa, T., Kawacytokines share the IL-4Ra chain) directly act on adipocyte progenitors, stimLee et al., Artis and colleagues moto, H., Furusawa, J., Ohtani, ulate their proliferation, and promote their differentiation toward beige adipoM., Fujii, H., and Koyasu, S. observed that administration cytes (Lee et al., 2015). Additionally, ILC2 produce the peptide MetEnk, which (2010). Nature 463, 540–544. / animals reof IL-33 to Il4ra can directly bind to the d1 opioid receptor expressed on white adipose tissue and thereby promote the generation of beige adipocytes (Brestoff et al., 2014). Nguyen, K.D., Qiu, Y., Cui, X., Goh, sulted in increased numbers However, it remains to be shown whether both pathways exist in parallel and Y.P., Mwangi, J., David, T., Muof UCP1+ adipocytes, sugwhich cells are targeted by MetEnk. While white adipocytes were shown to kundan, L., Brombacher, F., gesting a direct role of IL-33 inproduce IL-33, it is not clear whether they are the physiologically relevant Locksley, R.M., and Chawla, A. (2011). Nature 480, 104–108. source of this ILC2 activator. Pathways discovered in the featured articles dependent of IL-4 signaling. are shown in bold. Several lines of inquiry will Qiu, Y., Nguyen, K.D., Odegaard, need to be pursued to better J.I., Cui, X., Tian, X., Locksley, understand how ILC2 act on adipocytes. shown to produce IL-33, which can be R.M., Palmiter, R.D., and Chawla, A. (2014). Cell 157, 1292–1308. For example, it will be interesting to deter- increased by treatment with pro-inflammine the relative contribution of IL-4, IL- matory stimuli such as TNF (Wood et al., Wood, I.S., Wang, B., and Trayhurn, P. (2009). Bio13, and MetEnk to the beiging of WAT. 2009). However, it remains to be shown chem. Biophys. Res. Commun. 384, 105–109. From the above discussed publications, whether adipocytes themselves are the Wu, D., Molofsky, A.B., Liang, H.E., Ricardo-Gonit remained unclear as to whether both main source of IL-33 and how ILC2 affect zalez, R.R., Jouihan, H.A., Bando, J.K., Chawla, A., and Locksley, R.M. (2011). Science 332, 243–247. pathways act on the same cells or this endogenous feedback mechanism. whether there are multiple layers of regu- Lastly, it will be exciting to find how these Zeyda, M., Wernly, B., Demyanets, S., Kaun, C., Ha¨mmerle, M., Hantusch, B., Schranz, M., Neulation for the beiging of fat. Human pathways can be employed in order to hofer, A., Itariu, B.K., Keck, M., et al. (2013). Int. white adipose tissue adipocytes were increase IL-33 levels in vivo and pave J. Obes. (Lond.) 37, 658–665.

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Adipose tissue: ILC2 crank up the heat.

White-to-beige conversion of adipocytes is one of the most promising approaches to therapeutically target obesity; however, the signals driving this p...
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