Abstract
Although interleukin-6 (IL-6) has been regarded as a homeostatic regulator of fat metabolism, its role in brown adipose thermogenesis remains to be further clarified. By using wild-type (WT) and IL-6-knockout (KO) mice, this study aims to investigate whether IL-6 regulates the thermogenic capability of brown adipose tissue (BAT) at both young and elderly stages. We demonstrated that IL-6 KO enhances BAT thermogenesis at a young age, as evidenced by the increased mRNA and protein expression levels of thermogenic genes, and the elevated interscapular surface temperature. The IL-6-KO enhancement of BAT thermogenesis is associated with improved respiratory exchange ratio (RER) and glucose homeostasis at young stages. However, these improvements disappear in elderly KO mice, which is likely attributable to the highly increased expression of other inflammatory cytokines, such as Tnfα, Il-1β, and Il-10. Our findings indicate that the lack of IL-6 has a temporal-specific contribution to the promotion of BAT thermogenesis.
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References
Caballero B (2019) Humans against obesity: who will win? Adv Nutr 10:S4–S9. https://doi.org/10.1093/advances/nmy055
Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C et al (2017) Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 377:13–27. https://doi.org/10.1056/NEJMoa1614362
Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156:20–44. https://doi.org/10.1016/j.cell.2013.12.012
Poekes L, Lanthier N, Leclercq IA (2015) Brown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome. Clin Sci (Lond) 129:933–949. https://doi.org/10.1042/CS20150339
Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10:24–36. https://doi.org/10.1038/nrendo.2013.204
Boon MR, van MarkenLichtenbelt WD (2016) Brown adipose tissue: a human perspective. Handb Exp Pharmacol 233:301–319. https://doi.org/10.1007/164_2015_11
Fenzl A, Kiefer FW (2014) Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig 19:25–37. https://doi.org/10.1515/hmbci-2014-0022
Fernández-Verdejo R, Marlatt KL, Ravussin E, Galgani JE (2019) Contribution of brown adipose tissue to human energy metabolism. Mol Aspects Med 68:82–89. https://doi.org/10.1016/j.mam.2019.07.003
Porter C (2017) Quantification of UCP1 function in human brown adipose tissue. Adipocyte 6:67–174. https://doi.org/10.1080/21623945.2017.1319535
Richard MA, Pallubinsky H, Blondin DP (2020) Functional characterization of human brown adipose tissue metabolism. Biochem J 477:1261–1286. https://doi.org/10.1042/BCJ20190464
Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11:738–749. https://doi.org/10.1038/nri3071
Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356. https://doi.org/10.1079/pns2001110
Villarroya F, Cereijo R, Gavaldà-Navarro A, Villarroya J, Giralt M (2018) Inflammation of brown/beige adipose tissues in obesity and metabolic disease. J Intern Med 284:492–504. https://doi.org/10.1111/joim.12803
Alcalá M, Calderon-Dominguez M, Bustos E, Ramos P, Casals N, Serra D, Viana M, Herrero L (2017) Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice. Sci Rep 7:16082. https://doi.org/10.1038/s41598-017-16463-6
Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79. https://doi.org/10.1038/nm0102-75
Timper K, Denson JL, Steculorum SM, Heilinger C, Engström-Ruud L, Wunderlich CM, Rose-John S, Wunderlich FT, Brüning JC (2017) IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep 19:267–280. https://doi.org/10.1016/j.celrep.2017.03.043
Kristóf E, Klusóczki Á, Veress R, Shaw A, Combi ZS, Varga K, Győry F, Balajthy Z, Bai P, Bacso Z, Fésüs L (2019) Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp Cell Res 377:47–55. https://doi.org/10.1016/j.yexcr.2019.02.015
Qing H, Desrouleaux R, Israni-Winger K, Mineur YS, Fogelman N, Zhang C, Rashed S, Palm NW, Sinha R, Picciotto MR, Perry RJ, Wang A (2020) Origin and function of stress-induced IL-6 in murine models. Cell 182:1660. https://doi.org/10.1016/j.cell.2020.08.044
Matthews VB, Allen TL, Risis S, Chan MH, Henstridge DC, Watson N, Zaffino LA, Babb JR, Boon J, Meikle PJ, Jowett JB, Watt MJ, Jansson JO, Bruce CR, Febbraio MA (2010) Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53:2431–2441. https://doi.org/10.1007/s00125-010-1865-y
Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA et al (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430. https://doi.org/10.1038/ni.2865
Li G, Klein RL, Matheny M, King MA, Meyer EM, Scarpace PJ (2002) Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 115:879–889. https://doi.org/10.1016/s0306-4522(02)00447-5
Mishra D, Richard JE, Maric I, Porteiro B, Häring M, Kooijman S, Musovic S, Eerola K, López-Ferreras L, Peris E, Grycel K, Shevchouk OT, Micallef P, Olofsson CS, Wernstedt Asterholm I et al (2019) Parabrachial interleukin-6 reduces body weight and food intake and increases thermogenesis to regulate energy metabolism. Cell Rep 26:3011–3026. https://doi.org/10.1016/j.celrep.2019.02.044
Xu E, Pereira M, Karakasilioti I, Theurich S, Al-Maarri M, Rappl G, Waisman A, Wunderlich FT, Brüning JC (2017) Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance. Nat Commun 8:14803. https://doi.org/10.1038/ncomms14803
Theurich S, Tsaousidou E, Hanssen R, Lempradl AM, Mauer J, Timper K, Schilbach K, Folz-Donahue K, Heilinger C, Sexl V, Pospisilik JA, Wunderlich FT, Brüning JC (2017) IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab 26:171–184. https://doi.org/10.1016/j.cmet.2017.05.018
DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS et al (2013) B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A 110:5133–5138. https://doi.org/10.1073/pnas.1215840110
Omran F, Christian M (2020) Inflammatory signaling and brown fat activity. Front Endocrinol (Lausanne) 11:156. https://doi.org/10.3389/fendo.2020.00156
Rebiger L, Lenzen S, Mehmeti I (2016) Susceptibility of brown adipocytes to pro-inflammatory cytokine toxicity and reactive oxygen species. Biosci Rep 36:e00306. https://doi.org/10.1042/BSR20150193
Zhang Q, He M, Deng C, Wang H, Huang XF (2014) Effects of olanzapine on the elevation of macrophage infiltration and pro-inflammatory cytokine expression in female rats. J Psychopharmacol 28:1161–1169. https://doi.org/10.1177/0269881114555250
Cawthorn WP, Sethi JK (2008) TNF-alpha and adipocyte biology. FEBS lett 582:117–131. https://doi.org/10.1016/j.febslet.2007.11.051
Valladares A, Roncero C, Benito M, Porras A (2001) TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38 MAPK. FEBS lett 493:6–11. https://doi.org/10.1016/s0014-5793(01)02264-5
Goto T, Naknukool S, Yoshitake R, Hanafusa Y, Tokiwa S, Li Y, Sakamoto T, Nitta T, Kim M, Takahashi N, Yu R, Daiyasu H, Seno S, Matsuda H, Kawada T (2016) Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine 77:107–114. https://doi.org/10.1016/j.cyto.2015.11.001
Rajbhandari P, Thomas BJ, Feng AC, Hong C, Wang J, Vergnes L, Sallam T, Wang B, Sandhu J, Seldin MM, Lusis AJ, Fong LG, Katz M, Lee R, Young SG et al (2018) IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172:218–233. https://doi.org/10.1016/j.cell.2017.11.019
Funding
This work was supported by the grant from the Construction Engineering Special Fund of “Taishan Scholars” (No. 201511023, 201712022), the National Key Research and Development Program of China (2017YFE0129800), Funds of Shandong “Double Tops” Program, the Natural Science Foundation of Shandong Province, China (No. ZR2019MC016), and the Program for Scientific Research Innovation Team of Young Scholar in Colleges and Universities of Shandong Province (2019KJE009).
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Mei Dong, Cheng Gao, and Yanxin Jia performed experiments, wrote the manuscript, organized the literature and figures. Weijia Xu, Yan Liu, and Xin Wen performed experiments and contributed to discussion. Haifang Li, Hai Lin, and Qingxin Liu conceived the project, led and supervised the study, and reviewed/edited the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Key points
• IL-6 KO enhances brown fat thermogenesis in young mice.
• IL-6 KO improves RER and glucose homeostasis in young mice.
• The thermogenic and metabolic improvements disappear in elderly IL-6-KO mice.
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Dong, M., Gao, C., Jia, Y. et al. Temporal specificity of IL-6 knockout in enhancing the thermogenic capability of brown adipose tissue. J Physiol Biochem 78, 619–628 (2022). https://doi.org/10.1007/s13105-021-00847-4
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DOI: https://doi.org/10.1007/s13105-021-00847-4