Macrophage-Derived upd3 Cytokine Causes Impaired Glucose Homeostasis and Reduced Lifespan in Drosophila Fed a Lipid-Rich Diet

Abstract

Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved "scavenger receptor-JNK-type 1 cytokine" cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway.

References 62

1. 1.

   Agaisse H., Perrimon N. The roles of JAK/STAT signaling in Drosophila immune responses. Immunol. Rev. 2004;198:72-82.

   Not in our library10.1111/j.0105-2896.2004.0133.x

2. 2.

   Agaisse H., Petersen U.M., Boutros M., Mathey-Prevot B., Perrimon N. Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev. Cell. 2003;5:441-450.

   Not in our library10.1016/s1534-5807(03)00244-2

3. 3.

   Al-Anzi B., Zinn K. Colorimetric measurement of triglycerides cannot provide an accurate measure of stored fat content in Drosophila. PLoS ONE. 2010;5:e12353.

   Not in our library10.1371/journal.pone.0012353

4. 4.

   Alikhani N., Ferguson R.D., Novosyadlyy R., Gallagher E.J., Scheinman E.J., Yakar S., LeRoith D. Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene. 2013;32:961-967.

   Not in our library10.1038/onc.2012.113

5. 5.

   Arkan M.C., Hevener A.L., Greten F.R., Maeda S., Li Z.W., Long J.M., Wynshaw-Boris A., Poli G., Olefsky J., Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 2005;11:191-198.

   Not in our library10.1038/nm1185

6. 6.

   Bach E.A., Ekas L.A., Ayala-Camargo A., Flaherty M.S., Lee H., Perrimon N., Baeg G.H. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr. Patterns. 2007;7:323-331.

   Not in our library10.1016/j.modgep.2006.08.003

7. 7.

   Baranova I.N., Kurlander R., Bocharov A.V., Vishnyakova T.G., Chen Z., Remaley A.T., Csako G., Patterson A.P., Eggerman T.L. Role of human CD36 in bacterial recognition, phagocytosis, and pathogen-induced JNK-mediated signaling. J. Immunol. 2008;181:7147-7156.

   Not in our library10.4049/jimmunol.181.10.7147

8. 8.

   Betz A., Ryoo H.D., Steller H., Darnell J.E. STAT92E is a positive regulator of Drosophila inhibitor of apoptosis 1 (DIAP/1) and protects against radiation-induced apoptosis. Proc. Natl. Acad. Sci. USA. 2008;105:13805-13810.

   Not in our library10.1073/pnas.0806291105

9. 9.

   Binari R., Perrimon N. Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila. Genes Dev. 1994;8:300-312.

   Not in our library10.1101/gad.8.3.300

10. 10.

    Birse R.T., Choi J., Reardon K., Rodriguez J., Graham S., Diop S., Ocorr K., Bodmer R., Oldham S. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab. 2010;12:533-544.

    Not in our library10.1016/j.cmet.2010.09.014

11. 11.

    Biswas S.K., Mantovani A. Orchestration of metabolism by macrophages. Cell Metab. 2012;15:432-437.

    Not in our library10.1016/j.cmet.2011.11.013

12. 12.

    Brown S., Hu N., Hombría J.C. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 2001;11:1700-1705.

    Not in our library10.1016/s0960-9822(01)00524-3

13. 13.

    Buchon N., Broderick N.A., Poidevin M., Pradervand S., Lemaitre B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe. 2009;5:200-211.

    Not in our library10.1016/j.chom.2009.01.003

14. 14.

    Charroux B., Royet J. Elimination of plasmatocytes by targeted apoptosis reveals their role in multiple aspects of the Drosophila immune response. Proc. Natl. Acad. Sci. USA. 2009;106:9797-9802.

    Not in our library10.1073/pnas.0903971106

15. 15.

    Clark R.I., Woodcock K.J., Geissmann F., Trouillet C., Dionne M.S. Multiple TGF-beta superfamily signals modulate the adult Drosophila immune response. Curr. Biol. 2011;21:1672-1677.

    Not in our library10.1016/j.cub.2011.08.048

16. 16.
    MEF2 Is an In Vivo Immune-Metabolic Switch · 2013

    No notice
17. 17.

    Clementi A.H., Gaudy A.M., van Rooijen N., Pierce R.H., Mooney R.A. Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling. Biochim. Biophys. Acta. 2009;1792:1062-1072.

    Not in our library10.1016/j.bbadis.2009.08.007

18. 18.

    Dionne M.S., Pham L.N., Shirasu-Hiza M., Schneider D.S. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr. Biol. 2006;16:1977-1985.

    Not in our library10.1016/j.cub.2006.08.052

19. 19.

    Driver C.J., Cosopodiotis G. The effect of dietary fat on longevity of Drosophila melanogaster. Exp. Gerontol. 1979;14:95-100.

    Not in our library10.1016/0531-5565(79)90023-8

20. 20.
    Clodronate Liposomes Improve Metabolic Profile and Reduce Visceral Adipose Macrophage Content in Diet-Induced Obese Mice · 2011

    No notice
21. 21.

    Franc N.C., Heitzler P., Ezekowitz R.A., White K. Requirement for croquemort in phagocytosis of apoptotic cells in Drosophila. Science. 1999;284:1991-1994.

    Not in our library10.1126/science.284.5422.1991

22. 22.

    Gold K.S., Brückner K. Drosophila as a model for the two myeloid blood cell systems in vertebrates. Exp. Hematol. 2014;42:717-727.

    Not in our library10.1016/j.exphem.2014.06.002

23. 23.

    Goto A., Kumagai T., Kumagai C., Hirose J., Narita H., Mori H., Kadowaki T., Beck K., Kitagawa Y. A Drosophila haemocyte-specific protein, hemolectin, similar to human von Willebrand factor. Biochem. J. 2001;359:99-108.

    Not in our library10.1042/0264-6021:3590099

24. 24.

    Han M.S., Jung D.Y., Morel C., Lakhani S.A., Kim J.K., Flavell R.A., Davis R.J. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science. 2013;339:218-222.

    Not in our library10.1126/science.1227568

25. 25.
    Role of high-fat diet in stress response of Drosophila. · 2012

    Not checked
26. 26.

    Hirosumi J., Tuncman G., Chang L., Görgün C.Z., Uysal K.T., Maeda K., Karin M., Hotamisligil G.S. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333-336.

    Not in our library10.1038/nature01137

27. 27.

    Holz A., Bossinger B., Strasser T., Janning W., Klapper R. The two origins of hemocytes in Drosophila. Development. 2003;130:4955-4962.

    Not in our library10.1242/dev.00702

28. 28.

    Hou X.S., Melnick M.B., Perrimon N. Marelle acts downstream of the Drosophila HOP/JAK kinase and encodes a protein similar to the mammalian STATs. Cell. 1996;84:411-419.

    Not in our library10.1016/s0092-8674(00)81286-6

29. 29.

    Jamieson A.M., Pasman L., Yu S., Gamradt P., Homer R.J., Decker T., Medzhitov R. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science. 2013;340:1230-1234.

    Not in our library10.1126/science.1233632

30. 30.

    Jiang H., Patel P.H., Kohlmaier A., Grenley M.O., McEwen D.G., Edgar B.A. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell. 2009;137:1343-1355.

    Not in our library10.1016/j.cell.2009.05.014

31. 31.

    Jin C., Flavell R.A. Innate sensors of pathogen and stress: linking inflammation to obesity. J. Allergy Clin. Immunol. 2013;132:287-294.

    Not in our library10.1016/j.jaci.2013.06.022

32. 32.

    Karpac J., Younger A., Jasper H. Dynamic coordination of innate immune signaling and insulin signaling regulates systemic responses to localized DNA damage. Dev. Cell. 2011;20:841-854.

    Not in our library10.1016/j.devcel.2011.05.011

33. 33.

    Kohlmaier A., Edgar B.A. Proliferative control in Drosophila stem cells. Curr. Opin. Cell Biol. 2008;20:699-706.

    Not in our library10.1016/j.ceb.2008.10.002

34. 34.

    Kroenke C.H., Kwan M.L., Sweeney C., Castillo A., Caan B.J. High- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis. J. Natl. Cancer Inst. 2013;105:616-623.

    Not in our library10.1093/jnci/djt027

35. 35.

    Krzemień J., Dubois L., Makki R., Meister M., Vincent A., Crozatier M. Control of blood cell homeostasis in Drosophila larvae by the posterior signalling centre. Nature. 2007;446:325-328.

    Not in our library10.1038/nature05650

36. 36.

    Krzemień J., Oyallon J., Crozatier M., Vincent A. Hematopoietic progenitors and hemocyte lineages in the Drosophila lymph gland. Dev. Biol. 2010;346:310-319.

    Not in our library10.1016/j.ydbio.2010.08.003

37. 37.

    Kurucz E., Márkus R., Zsámboki J., Folkl-Medzihradszky K., Darula Z., Vilmos P., Udvardy A., Krausz I., Lukacsovich T., Gateff E., et al. Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes. Curr. Biol. 2007;17:649-654.

    Not in our library10.1016/j.cub.2007.02.041

38. 38.

    Lebestky T., Chang T., Hartenstein V., Banerjee U. Specification of Drosophila hematopoietic lineage by conserved transcription factors. Science. 2000;288:146-149.

    Not in our library10.1126/science.288.5463.146

39. 39.

    Lemaitre B., Nicolas E., Michaut L., Reichhart J.M., Hoffmann J.A. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973-983.

    Not in our library10.1016/s0092-8674(00)80172-5

40. 40.

    Li A.C., Glass C.K. The macrophage foam cell as a target for therapeutic intervention. Nat. Med. 2002;8:1235-1242.

    Not in our library10.1038/nm1102-1235

41. 41.

    McGuire S.E., Mao Z., Davis R.L. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci. STKE. 2004;2004:pl6.

    Not in our library10.1126/stke.2202004pl6

42. 42.

    Medzhitov R., Schneider D.S., Soares M.P. Disease tolerance as a defense strategy. Science. 2012;335:936-941.

    Not in our library10.1126/science.1214935

43. 43.

    Meister M. Blood cells of Drosophila: cell lineages and role in host defence. Curr. Opin. Immunol. 2004;16:10-15.

    Not in our library10.1016/j.coi.2003.11.002

44. 44.

    Moore K.J., Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341-355.

    Not in our library10.1016/j.cell.2011.04.005

45. 45.

    Olefsky J.M. IKKepsilon: a bridge between obesity and inflammation. Cell. 2009;138:834-836.

    Not in our library10.1016/j.cell.2009.08.018

46. 46.

    Orr J.S., Puglisi M.J., Ellacott K.L., Lumeng C.N., Wasserman D.H., Hasty A.H. Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes. 2012;61:2718-2727.

    Not in our library10.2337/db11-1595

47. 47.

    Osman D., Buchon N., Chakrabarti S., Huang Y.T., Su W.C., Poidevin M., Tsai Y.C., Lemaitre B. Autocrine and paracrine unpaired signaling regulate intestinal stem cell maintenance and division. J. Cell Sci. 2012;125:5944-5949.

    Not in our library10.1242/jcs.113100

48. 48.

    Rahaman S.O., Lennon D.J., Febbraio M., Podrez E.A., Hazen S.L., Silverstein R.L. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006;4:211-221.

    Not in our library10.1016/j.cmet.2006.06.007

49. 49.

    Rajan A., Perrimon N. Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell. 2012;151:123-137.

    Not in our library10.1016/j.cell.2012.08.019

50. 50.

    Reilly J.J., Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes (Lond). 2011;35:891-898.

    Not in our library10.1038/ijo.2010.222

51. 51.

    Reilly S.M., Chiang S.H., Decker S.J., Chang L., Uhm M., Larsen M.J., Rubin J.R., Mowers J., White N.M., Hochberg I., et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nat. Med. 2013;19:313-321.

    Not in our library10.1038/nm.3082

52. 52.

    Robertson H.T., Smith D.L., Pajewski N.M., Weindruch R.H., Garland T., Argyropoulos G., Bokov A., Allison D.B. Can rodent longevity studies be both short and powerful? J. Gerontol. A Biol. Sci. Med. Sci. 2011;66:279-286.

    Not in our library10.1093/gerona/glq190

53. 53.

    Saberi M., Woods N.B., de Luca C., Schenk S., Lu J.C., Bandyopadhyay G., Verma I.M., Olefsky J.M. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 2009;10:419-429.

    Not in our library10.1016/j.cmet.2009.09.006

54. 54.

    Singh S.R., Liu W., Hou S.X. The adult Drosophila malpighian tubules are maintained by multipotent stem cells. Cell Stem Cell. 2007;1:191-203.

    Not in our library10.1016/j.stem.2007.07.003

55. 55.

    Spann N.J., Garmire L.X., McDonald J.G., Myers D.S., Milne S.B., Shibata N., Reichart D., Fox J.N., Shaked I., Heudobler D., et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell. 2012;151:138-152.

    Not in our library10.1016/j.cell.2012.06.054

56. 56.

    Stuart L.M., Deng J., Silver J.M., Takahashi K., Tseng A.A., Hennessy E.J., Ezekowitz R.A., Moore K.J. Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J. Cell Biol. 2005;170:477-485.

    Not in our library10.1083/jcb.200501113

57. 57.

    Szendroedi J., Roden M. Ectopic lipids and organ function. Curr. Opin. Lipidol. 2009;20:50-56.

    Not in our library10.1097/mol.0b013e328321b3a8

58. 58.
    Implication of inflammatory signaling pathways in obesity-induced insulin resistance · 2013

    No notice
59. 59.

    van Herpen N.A., Schrauwen-Hinderling V.B. Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol. Behav. 2008;94:231-241.

    Not in our library10.1016/j.physbeh.2007.11.049

60. 60.

    Wagener A., Müller U., Brockmann G.A. The age of attaining highest body weight correlates with lifespan in a genetically obese mouse model. Nutr Diabetes. 2013;3:e62.

    Not in our library10.1038/nutd.2013.4

61. 61.

    White K., Tahaoglu E., Steller H. Cell killing by the Drosophila gene reaper. Science. 1996;271:805-807.

    Not in our library10.1126/science.271.5250.805

62. 62.

    Yan R., Small S., Desplan C., Dearolf C.R., Darnell J.E. Identification of a Stat gene that functions in Drosophila development. Cell. 1996;84:421-430.

    Not in our library10.1016/s0092-8674(00)81287-8

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