Adipocyte-macrophage crosstalk plays a critical role to regulate adipose tissue microenvironment and cause chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes, however, little is known about its role in metabolic disorders. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. In addition, IL-29 promoted monocyte/macrophage migration. Inhibition of IL-29 could reduce inflammatory cytokine production in macrophage-adipocyte coculture system, which mimic an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for treating obesity and insulin resistance in patients with metabolic disorders.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $28.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nguyen, D. M. & El-Serag, H. B. The epidemiology of obesity. Gastroenterol. Clin. N. Am. 39, 1–7 (2010).
Collaboration NCDRF. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387, 1377–1396 (2016).
Maffetone, P. B., Rivera-Dominguez, I. & Laursen, P. B. Overfat and underfat: new terms and definitions long overdue. Front. Public Health 4, 279 (2016).
Kelly, T., Yang, W., Chen, C. S., Reynolds, K. & He, J. Global burden of obesity in 2005 and projections to 2030. Int J. Obes. (Lond.) 32, 1431–1437 (2008).
Patel, D. Pharmacotherapy for the management of obesity. Metabolism 64, 1376–1385 (2015).
Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).
Kim, J. B. Dynamic cross talk between metabolic organs in obesity and metabolic diseases. Exp. Mol. Med. 48, e214 (2016).
Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Investig. 116, 1793–1801 (2006).
Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu Rev. Immunol. 29, 415–445 (2011).
Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).
Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).
Hotamisligil, G., Shargill, N. & Spiegelman, B. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).
Kern, P. A., Ranganathan, S., Li, C., Wood, L. & Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 280, E745–E751 (2001).
Kim, C. S. et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J. Obes. (Lond.) 30, 1347–1355 (2006).
Moschen, A. R. et al. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol. Med. 17, 840–845 (2011).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
Panee, J. Monocyte chemoattractant protein 1 (MCP-1) in obesity and diabetes. Cytokine 60, 1–12 (2012).
Lackey, D. E. & Olefsky, J. M. Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28 (2016).
Khan, A. & Pessin, J. Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. Diabetologia 45, 1475–1483 (2002).
Rotter, V., Nagaev, I. & Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J. Biol. Chem. 278, 45777–45784 (2003).
Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat. Immunol. 4, 63–68 (2003).
Kotenko, S. V. et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat. Immunol. 4, 69–77 (2003).
Wolk, K. et al. Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes. J. Leukoc. Biol. 83, 1181–1193 (2008).
Wolk, K. et al. IL-29 is produced by T(H)17 cells and mediates the cutaneous antiviral competence in psoriasis. Sci. Transl. Med. 5, 204ra129 (2013).
Siren, J., Pirhonen, J., Julkunen, I. & Matikainen, S. IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J. Immunol. 174, 1932–1937 (2005).
Kelm, N. E. et al. The role of IL-29 in immunity and cancer. Crit. Rev. Oncol. Hematol. 106, 91–98 (2016).
Wang, F. et al. Interleukin-29 modulates proinflammatory cytokine production in synovial inflammation of rheumatoid arthritis. Arthritis Res. Ther. 14, R228 (2012).
Li, Y. et al. Adenovirus expressing IFN-lambda1 (IL-29) attenuates allergic airway inflammation and airway hyperreactivity in experimental asthma. Int. Immunopharmacol. 21, 156–162 (2014).
Wabitsch, M. et al. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J. Obes. Relat. Metab. Disord. 25, 8–15 (2001).
Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 112, 1796–1808 (2003).
Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Investig. 117, 175–184 (2007).
Sirén, J., Pirhonen, J., Julkunen, I. & Matikainen, S. IFN-α Regulates TLR-Dependent Gene Expression of IFN-α, IFN-β, IL-28, and IL-29. J. Immunol. 174, 1932–1937 (2005).
Keuper, M., Dzyakanchuk, A., Amrein, K. E., Wabitsch, M. & Fischer-Posovszky, P. THP-1 macrophages and SGBS adipocytes – a new human in vitro model system of inflamed adipose tissue. Front. Endocrinol. 2, 89 (2011).
Hotamisligil, G. S. & Bernlohr, D. A. Metabolic functions of FABPs-mechanisms and therapeutic implications. Nat. Rev. Endocrinol. 11, 592–605 (2015).
Koppen, A. & Kalkhoven, E. Brown vs white adipocytes: the PPARgamma coregulator story. FEBS Lett. 584, 3250–3259 (2010).
Lehrke, M. & Lazar, M. A. The many faces of PPARgamma. Cell 123, 993–999 (2005).
Schoonjans, K. et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15, 5336–5348 (1996).
Matsuki, T., Horai, R., Sudo, K. & Iwakura, Y. IL-1 Plays an important role in lipid metabolism by regulating insulin levels under physiological conditions. J. Exp. Med. 198, 877–888 (2003).
Glund, S. & Krook, A. Role of interleukin-6 signalling in glucose and lipid metabolism. Acta Physiol. (Oxf.) 192, 37–48 (2008).
Jovinge, S. et al. Evidence for a role of tumor necrosis factor alpha in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism 47, 113–118 (1998).
Nov, O. et al. Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability. PLoS One 8, e53626 (2013).
Kawakami, M. et al. Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J. Biochem. 101, 331–338 (1987).
Hardardottir, I., Moser, A. H., Memon, R., Grunfeld, C. & Feingold, K. R. Effects of TNF, IL-1, and the combination of both cytokines on cholesterol metabolism in Syrian hamsters. Lymphokine Cytokine Res. 13, 161–166 (1994).
Greenberg, A. S. et al. Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Res. 52, 4113–4116 (1992).
Hammond, M. E. et al. IL-8 induces neutrophil chemotaxis predominantly via type I IL-8 receptors. J. Immunol. 155, 1428–1433 (1995).
Turner, M. D., Nedjai, B., Hurst, T. & Pennington, D. J. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim. Biophys. Acta 1843, 2563–2582 (2014).
Bonecchi, R. et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J. Immunol. 164, 3862–3869 (2000).
Preobrazhensky, A. A. et al. Monocyte chemotactic protein-1 receptor CCR2B is a glycoprotein that has tyrosine sulfation in a conserved extracellular N-terminal region. J. Immunol. 165, 5295–5303 (2000).
Blazek, K. et al. IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1beta production. J. Exp. Med. 212, 845–853 (2015).
Chrysanthopoulou, A. et al. Interferon lambda1/IL-29 and inorganic polyphosphate are novel regulators of neutrophil-driven thromboinflammation. J. Pathol. 243, 111–122 (2017).
Juge-Aubry, C. E. et al. Adipose tissue is a regulated source of interleukin-10. Cytokine 29, 270–274 (2005).
Walter, M. R. The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr. Top. Microbiol. Immunol. 380, 191–212 (2014).
Liu, B. S., Janssen, H. L. & Boonstra, A. Type I and III interferons enhance IL-10R expression on human monocytes and macrophages, resulting in IL-10-mediated suppression of TLR-induced IL-12. Eur. J. Immunol. 42, 2431–2440 (2012).
Liu, B. S., Janssen, H. L. & Boonstra, A. IL-29 and IFNalpha differ in their ability to modulate IL-12 production by TLR-activated human macrophages and exhibit differential regulation of the IFNgamma receptor expression. Blood 117, 2385–2395 (2011).
Strissel, K. J. et al. T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity 18, 1918–1925 (2010).
Dai, J., Megjugorac, N. J., Gallagher, G. E., Yu, R. Y. & Gallagher, G. IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells. Blood 113, 5829–5838 (2009).
Singh, S. et al. Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: a systematic review and meta-analysis. PLoS One 13, e0195123 (2018).
Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. & Taylor, R. Effects of an engineered human anti–TNF-α antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45, 881–885 (1996).
Aharon-Hananel, G., Jörns, A., Lenzen, S., Raz, I. & Weksler-Zangen, S. Antidiabetic effect of interleukin-1β antibody therapy through β-cell protection in the Cohen diabetes-sensitive rat. Diabetes 64, 1780–1785 (2015).
Owyang, A. M. et al. XOMA 052, an anti-IL-1β monoclonal antibody, improves glucose control and β-cell function in the diet-induced obesity mouse model. Endocrinology 151, 2515–2527 (2010).
Hagberg, C. E. et al. Flow cytometry of mouse and human adipocytes for the analysis of browning and cellular heterogeneity. Cell Rep. 24, 2746–2756 (2018).
We are grateful to Professor Martin Wabitsch (University of Ulm, Germany) and Professor Peter Staeheli (Medical Center University of Freiburg, Germany) for kindly providing SGBS preadipocyte cell line and IL-28R1−/− mice, respectively. This work was supported by the Ministry of Science and Technology of Taiwan (MOST-106-2311-B-006-008-MY2 and MOST-108-2320-B-006-052).
The authors declare no competing interests.