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Frontiers of Medicine

, Volume 9, Issue 2, pp 139–145 | Cite as

Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes

  • Jianping Ye
Review

Abstract

In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the proinflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-κB. IL-15 binds to its receptor that contains three different subunits (α, β and γ) to activate JAK/STAT, PI3K/Akt, IKK/NF-κB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti-obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure.

Keywords

inflammation obesity cytokine energy expenditure insulin resistance 

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References

  1. 1.
    Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444(7121): 860–867CrossRefPubMedGoogle Scholar
  2. 2.
    Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev 2007; 21(12): 1443–1455CrossRefPubMedGoogle Scholar
  3. 3.
    Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72(1): 219–246CrossRefPubMedGoogle Scholar
  4. 4.
    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11(2): 98–107CrossRefPubMedGoogle Scholar
  5. 5.
    Saltiel AR. Insulin resistance in the defense against obesity. Cell Metab 2012; 15(6): 798–804CrossRefPubMedGoogle Scholar
  6. 6.
    De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fatrich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005; 146(10): 4192–4199CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKβ/NF-kB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008; 135(1): 61–73CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Brüning JC. MyD88 signaling in the CNS is required for development of fatty acidinduced leptin resistance and diet-induced obesity. Cell Metab 2009; 10(4): 249–259CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 2011; 121(5): 1858–1870CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): 457–461CrossRefPubMedGoogle Scholar
  11. 11.
    Lee YS, Kim JW, Osborne O, Oh Y, Sasik R, Schenk S, Chen A, Chung H, Murphy A, Watkins SM, Quehenberger O, Johnson RS, Olefsky JM. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity. Cell 2014; 157(6): 1339–1352CrossRefPubMedGoogle Scholar
  12. 12.
    Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 2014; 157(6): 1292–1308CrossRefPubMedGoogle Scholar
  13. 13.
    Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014; 157(6): 1279–1291CrossRefPubMedGoogle Scholar
  14. 14.
    Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am J Physiol Endocrinol Metab 2013; 304(5): E466–E477CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148(5): 852–871CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell 2013; 152(4): 673–684CrossRefPubMedGoogle Scholar
  17. 17.
    Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8(8): 457–465CrossRefPubMedGoogle Scholar
  18. 18.
    Ye J. Mechanisms of insulin resistance in obesity. Front Med 2013; 7(1): 14–24CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813(5): 878–888CrossRefPubMedGoogle Scholar
  20. 20.
    Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood 2001; 97(1): 14–32CrossRefPubMedGoogle Scholar
  21. 21.
    Azimi N, Brown K, Bamford RN, Tagaya Y, Siebenlist U, Waldmann TA. Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kB site. Proc Natl Acad Sci USA 1998; 95(5): 2452–2457CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Washizu J, Nishimura H, Nakamura N, Nimura Y, Yoshikai Y. The NF-kB binding site is essential for transcriptional activation of the IL-15 gene. Immunogenetics 1998; 48(1): 1–7CrossRefPubMedGoogle Scholar
  23. 23.
    Tamura Y, Watanabe K, Kantani T, Hayashi J, Ishida N, Kaneki M. Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr J 2011; 58(3): 211–215CrossRefPubMedGoogle Scholar
  24. 24.
    Quinn LS, Anderson BG, Conner JD, Wolden-Hanson T. IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARδ, SIRT1, PGC-1α, and PGC-1β expression in male mice. Endocrinology 2013; 154(1): 232–245CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Vijayakumar A, Wu Y, Sun H, Li X, Jeddy Z, Liu C, Schwartz GJ, Yakar S, LeRoith D. Targeted loss of GHR signaling in mouse skeletal muscle protects against high-fat diet-induced metabolic deterioration. Diabetes 2012; 61(1): 94–103CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Hiromatsu T, Yajima T, Matsuguchi T, Nishimura H, Wajjwalku W, Arai T, Nimura Y, Yoshikai Y. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-α-induced apoptosis. J Infect Dis 2003; 187(9): 1442–1451CrossRefPubMedGoogle Scholar
  27. 27.
    Orinska Z, Maurer M, Mirghomizadeh F, Bulanova E, Metz M, Nashkevich N, Schiemann F, Schulmistrat J, Budagian V, Giron-Michel J, Brandt E, Paus R, Bulfone-Paus S. IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nat Med 2007; 13(8): 927–934CrossRefPubMedGoogle Scholar
  28. 28.
    Budagian V, Bulanova E, Paus R, Bulfone-Paus S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 2006; 17(4): 259–280CrossRefPubMedGoogle Scholar
  29. 29.
    Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM. Identification and cloning of a novel IL-15 binding protein that is structurally related to the α chain of the IL-2 receptor. EMBO J 1995; 14(15): 3654–3663PubMedCentralPubMedGoogle Scholar
  30. 30.
    Quinn LS, Anderson BG. Interleukin-15, IL-15 receptor-α, and obesity: concordance of laboratory animal and human genetic studies. J Obesity 2011; 2011: 456347CrossRefGoogle Scholar
  31. 31.
    Vallabhapurapu S, Powolny-Budnicka I, Riemann M, Schmid RM, Paxian S, Pfeffer K, Körner H, Weih F. Rel/NF-κB family member RelA regulates NK1.1 to NK1.1+ transition as well as IL-15-induced expansion of NKT cells. Eur J Immunol 2008; 38(12): 3508–3519CrossRefPubMedGoogle Scholar
  32. 32.
    McDonald PP, Russo MP, Ferrini S, Cassatella MA. Interleukin-15 (IL-15) induces NF-kB activation and IL-8 production in human neutrophils. Blood 1998; 92(12): 4828–4835PubMedGoogle Scholar
  33. 33.
    Chenoweth MJ, Mian MF, Barra NG, Alain T, Sonenberg N, Bramson J, Lichty BD, Richards CD, Ma A, Ashkar AA. IL-15 can signal via IL-15Rα, JNK, and NF-κB to drive RANTES production by myeloid cells. J Immunol 2012; 188(9): 4149–4157CrossRefPubMedGoogle Scholar
  34. 34.
    Stone KP, Kastin AJ, Pan W. NFkB is an unexpected major mediator of interleukin-15 signaling in cerebral endothelia. Cell Physiol Biochem 2011; 28(1): 115–124CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Giron-Michel J, Caignard A, Fogli M, Brouty-Boyé D, Briard D, van Dijk M, Meazza R, Ferrini S, Lebousse-Kerdilès C, Clay D, Bompais H, Chouaib S, Péault B, Azzarone B. Differential STAT3, STAT5, and NF-kB activation in human hematopoietic progenitors by endogenous interleukin-15: implications in the expression of functional molecules. Blood 2003; 102(1): 109–117CrossRefPubMedGoogle Scholar
  36. 36.
    Nielsen AR, Hojman P, Erikstrup C, Fischer CP, Plomgaard P, Mounier R, Mortensen OH, Broholm C, Taudorf S, Krogh-Madsen R, Lindegaard B, Petersen AM, Gehl J, Pedersen BK. Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J Clin Endocrinol Metab 2008; 93(11): 4486–4493CrossRefPubMedGoogle Scholar
  37. 37.
    Carbó N, López-Soriano J, Costelli P, Alvarez B, Busquets S, Baccino FM, Quinn LS, López-Soriano FJ, Argilés JM. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim Biophys Acta 2001; 1526(1): 17–24CrossRefPubMedGoogle Scholar
  38. 38.
    Quinn LS, Anderson BG, Strait-Bodey L, Stroud AM, Argilés JM. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am J Physiol Endocrinol Metab 2009; 296(1): E191–E202CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Barra NG, Reid S, MacKenzie R, Werstuck G, Trigatti BL, Richards C, Holloway AC, Ashkar AA. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity (Silver Spring) 2010; 18(8): 1601–1607CrossRefGoogle Scholar
  40. 40.
    Alvarez B, Carbó N, López-Soriano J, Drivdahl RH, Busquets S, López-Soriano FJ, Argilés JM, Quinn LS. Effects of interleukin-15 (IL-15) on adipose tissue mass in rodent obesity models: evidence for direct IL-15 action on adipose tissue. Biochim Biophys Acta 2002; 1570(1): 33–37CrossRefPubMedGoogle Scholar
  41. 41.
    Almendro V, Fuster G, Busquets S, Ametller E, Figueras M, Argilés JM, López-Soriano FJ. Effects of IL-15 on rat brown adipose tissue: uncoupling proteins and PPARs. Obesity (Silver Spring) 2008; 16(2): 285–289CrossRefGoogle Scholar
  42. 42.
    Almendro V, Busquets S, Ametller E, Carbó N, Figueras M, Fuster G, Argilés JM, López-Soriano FJ. Effects of interleukin-15 on lipid oxidation: disposal of an oral [(14)C]-triolein load. Biochim Biophys Acta 2006; 1761(1): 37–42CrossRefPubMedGoogle Scholar
  43. 43.
    López-Soriano J, Carbó N, Almendro V, Figueras M, Ribas V, Busquets S, López-Soriano FJ, Argilés JM. Rat liver lipogenesis is modulated by interleukin-15. Int J Mol Med 2004; 13(6): 817–819PubMedGoogle Scholar
  44. 44.
    Barra NG, Chew MV, Holloway AC, Ashkar AA. Interleukin-15 treatment improves glucose homeostasis and insulin sensitivity in obese mice. Diabetes Obes Metab 2012; 14(2): 190–193CrossRefPubMedGoogle Scholar
  45. 45.
    Barra NG, Chew MV, Reid S, Ashkar AA. Interleukin-15 treatment induces weight loss independent of lymphocytes. PLoS ONE 2012; 7(6): e39553CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research CenterLouisiana State University SystemBaton RougeUSA

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