Interleukin-15 (IL-15) is a cytokine which inhibits lipid deposition in cultured adipocytes and decreases adipose tissue deposition in laboratory rodents. In human subjects, negative correlations between circulating IL-15 levels and both total and abdominal fat have been demonstrated. Deletions of IL15 in humans and mice are associated with obesity, while gain-of-function IL-15 overexpressing mice are resistant to diet-induced obesity. IL-15 is highly (but not exclusively) expressed at the mRNA level in skeletal muscle tissue, and the regulation of IL-15 translation and secretion is complex. Conflicting evidence exists concerning whether circulating IL-15 is released from skeletal muscle tissue in response to exercise or other physiological stimuli. The IL-15 receptor-alpha (IL-15Rα) subunit has a complex biochemistry, encoding both membrane-bound and soluble forms which can modulate IL-15 secretion and bioactivity. The gene encoding this receptor, IL15RA, resides on human chromosome 10p, a location linked to obesity and type-2 diabetes. Several single-nucleotide polymorphisms (SNPs) in human IL15RA and IL15 correlate with adiposity and markers of the metabolic syndrome. Genetic variation in IL15RA may modulate IL-15 bioavailability, which in turn regulates adiposity. Thus, IL-15 and the IL-15Rα may be novel targets for pharmacologic control of obesity in the human population. 1. Introduction The increased incidence of obesity in both developed and developing nations is a major public health problem [1]. Altered energy balance resulting in obesity is believed to be causal in the development of the metabolic syndrome and type-2 diabetes mellitus, conditions whose incidence is also rising at alarming rates [2, 3]. The economic burden of obesity and diabetes in the U.S. is currently in excess of $200 billion annually, and it is expected to rise [1]. Diet and lifestyle modifications are often unsuccessful in reducing obesity [4–6], and presently available pharmacologic treatments are problematic due to serious adverse effects [7]. Therefore, research involving novel pathways to control adiposity is warranted. Here, evidence that interleukin-15 (IL-15) can inhibit adipose tissue deposition in both laboratory animals and human subjects will be reviewed. Additionally, the complex regulation of IL-15 expression and secretion will be summarized. The specific receptor for IL-15, IL-15 receptor-alpha (IL-15Rα), appears to regulate IL-15 secretion, stability, and activity [8, 9]. Several single-nucleotide polymorphisms (SNPs) in human IL15 and IL15RA have been
References
[1]
J. O. Hill, H. R. Wyatt, G. W. Reed, and J. C. Peters, “Obesity and the environment: where do we go from here?” Science, vol. 299, no. 5608, pp. 853–855, 2003.
[2]
S. E. Kahn, R. L. Hull, and K. M. Utzschneider, “Mechanisms linking obesity to insulin resistance and type 2 diabetes,” Nature, vol. 444, no. 7121, pp. 840–846, 2006.
[3]
M. I. Harris, K. M. Flegal, C. C. Cowie et al., “Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: the Third National Health and Nutrition Examination Survey, 1988–1994,” Diabetes Care, vol. 21, no. 4, pp. 518–524, 1998.
[4]
M. Rosenbaum, H. R. Kissileff, L. E. S. Mayer, J. Hirsch, and R. L. Leibel, “Energy intake in weight-reduced humans,” Brain Research, vol. 1350, pp. 95–102, 2010.
[5]
M. W. Schwartz, S. C. Woods, R. J. Seeley, G. S. Barsh, D. G. Baskin, and R. L. Leibel, “Is the energy homeostasis system inherently biased toward weight gain?” Diabetes, vol. 52, no. 2, pp. 232–238, 2003.
[6]
R. Dalle Grave, S. Calugi, E. Centis, R. Marzocchi, M. El Ghoch, and G. Marchesini, “Lifestyle modification in the management of the metabolic syndrome: achievements and challenges,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 3, pp. 373–385, 2010.
[7]
A. Astrup, “Drug management of obesity—efficacy versus safety,” The New England Journal of Medicine, vol. 363, no. 3, pp. 288–290, 2010.
[8]
C. Bergamaschi, M. Rosati, R. Jalah et al., “Intracellular interaction of interleukin-15 with its receptor α during production leads to mutual stabilization and increased bioactivity,” Journal of Biological Chemistry, vol. 283, no. 7, pp. 4189–4199, 2008.
[9]
E. Bulanova, V. Budagian, E. Duitman et al., “Soluble interleukin (IL)-15Rα is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15,” Journal of Biological Chemistry, vol. 282, no. 18, pp. 13167–13179, 2007.
[10]
S. E. Riechman, G. Balasekaran, S. M. Roth, and R. E. Ferrell, “Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses,” Journal of Applied Physiology, vol. 97, no. 6, pp. 2214–2219, 2004.
[11]
E. E. Pistilli, J. M. Devaney, H. Gordish-Dressman et al., “Interleukin-15 and interleukin-15Rα SNPs and associations with muscle, bone, and predictors of the metabolic syndrome,” Cytokine, vol. 43, no. 1, pp. 45–53, 2008.
[12]
L. Di Renzo, M. Bigioni, F. G. Bottini et al., “Normal weight obese syndrome: role of single nucleotide polymorphism of IL-15Rα and MTHFR genes in the relationship between body composition and resting metabolic rate,” European Review for Medical and Pharmacological Sciences, vol. 10, no. 5, pp. 235–245, 2006.
[13]
N. Carbó, J. López-Soriano, P. Costelli et al., “Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control,” Biochimica et Biophysica Acta, vol. 1526, no. 1, pp. 17–24, 2001.
[14]
L. S. Quinn, L. Strait-Bodey, B. G. Anderson, J. M. Argilés, and P. J. Havel, “Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway,” Cell Biology International, vol. 29, no. 6, pp. 449–457, 2005.
[15]
A. R. Nielsen, P. Hojman, C. Erikstrup et al., “Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 11, pp. 4486–4493, 2008.
[16]
B. K. Pedersen, “The diseasome of physical inactivity - and the role of myokines in muscle-fat cross talk,” Journal of Physiology, vol. 587, no. 23, pp. 5559–5568, 2009.
[17]
K. H. Grabstein, J. Eisenman, K. Shanebeck et al., “Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor,” Science, vol. 264, no. 5161, pp. 965–968, 1994.
[18]
T. A. Fehniger and M. A. Caligiuri, “Interleukin 15: biology and relevance to human disease,” Blood, vol. 97, no. 1, pp. 14–32, 2001.
[19]
V. Budagian, E. Bulanova, R. Paus, and S. Bulfone-Paus, “IL-15/IL-15 receptor biology: a guided tour through an expanding universe,” Cytokine & Growth Factor Reviews, vol. 17, no. 4, pp. 259–280, 2006.
[20]
N. D. Horseman and L. Y. Yu-Lee, “Transcriptional regulation by the helix bundle peptide hormones: growth hormone, prolactin, and hematopoietic cytokines,” Endocrine Reviews, vol. 15, no. 5, pp. 627–649, 1994.
[21]
S. Verma, S. E. Hiby, Y. W. Loke, and A. King, “Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15,” Biology of Reproduction, vol. 62, no. 4, pp. 959–968, 2000.
[22]
A. L. Angiolillo, H. Kanegane, C. Sgadari, G. H. Reaman, and G. Tosato, “Interleukin-15 promotes angiogenesis in vivo,” Biochemical and Biophysical Research Communications, vol. 233, no. 1, pp. 231–237, 1997.
[23]
L. S. Quinn, B. G. Anderson, R. H. Drivdahl, B. Alvarez, and J. M. Argilés, “Overexpression of interleukin-15 induces skeletal muscle hypertrophy in vitro: implications for treatment of muscle wasting disorders,” Experimental Cell Research, vol. 280, no. 1, pp. 55–63, 2002.
[24]
K. M. Ajuwon, S. K. Jacobi, J. L. Kuske, and M. E. Spurlock, “Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-γ in primary pig adipocytes,” American Journal of Physiology, vol. 286, no. 3, pp. R547–R553, 2004.
[25]
L. S. Quinn, B. G. Anderson, L. Strait-Bodey, and T. Wolden-Hanson, “Serum and muscle interleukin-15 levels decrease in aging mice: correlation with declines in soluble interleukin-15 receptor alpha expression,” Experimental Gerontology, vol. 45, no. 2, pp. 106–112, 2010.
[26]
B. Toth, T. Haufe, C. Scholz et al., “Placental interleukin-15 expression in recurrent miscarriage,” American Journal of Reproductive Immunology, vol. 64, no. 6, pp. 402–410, 2010.
[27]
S. S. W. Chow, M. E. Craig, C. A. Jones et al., “Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection,” Cytokine, vol. 44, no. 1, pp. 78–84, 2008.
[28]
Y. Tagaya, G. Kurys, T. A. Thies et al., “Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 26, pp. 14444–14449, 1997.
[29]
A. Onu, T. Pohl, H. Krause, and S. Bulfone-Paus, “Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms,” Journal of Immunology, vol. 158, no. 1, pp. 255–262, 1997.
[30]
R. Meazza, A. Gaggero, F. Neglia et al., “Expression of two interleukin-15 mRNA isoforms in human tumors does not correlate with secretion: role of different signal peptides,” European Journal of Immunology, vol. 27, no. 5, pp. 1049–1054, 1997.
[31]
R. N. Bamford, A. P. DeFilippis, N. Azimi, G. Kurys, and T. A. Waldmann, “The 5' untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control,” Journal of Immunology, vol. 160, no. 9, pp. 4418–4426, 1998.
[32]
H. Nishimura, J. Washizu, N. Nakamura, A. Enomoto, and Y. Yoshikai, “Translational efficiency is up-regulated by alternative exon in murine IL-15 mRNA,” Journal of Immunology, vol. 160, no. 2, pp. 936–942, 1998.
[33]
Y. Tagaya, R. N. Bamford, A. P. DeFilippis, and T. A. Waldmann, “IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels,” Immunity, vol. 4, no. 4, pp. 329–336, 1996.
[34]
S. P. Weisberg, D. McCann, M. Desai, M. Rosenbaum, R. L. Leibel, and A. W. Ferrante Jr., “Obesity is associated with macrophage accumulation in adipose tissue,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1796–1808, 2003.
[35]
H. Xu, G. T. Barnes, Q. Yang et al., “Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance,” Journal of Clinical Investigation, vol. 112, no. 12, pp. 1821–1830, 2003.
[36]
X. Sun and M. B. Zemel, “Calcium and 1,25-dihydroxyvitamin D3 regulation of adipokine expression,” Obesity, vol. 15, no. 2, pp. 340–348, 2007.
[37]
D. M. Anderson, L. Johnson, M. B. Glaccum et al., “Chromosomal assignment and genomic structure of Il15,” Genomics, vol. 25, no. 3, pp. 701–706, 1995.
[38]
K. Wang, W.-D. Li, J. T. Glessner, S. F. A. Grant, H. Hakonarson, and R. A. Price, “Large copy-number variations are enriched in cases with moderate to extreme obesity,” Diabetes, vol. 59, no. 10, pp. 2690–2694, 2010.
[39]
L. P. Kozak and R. Anunciado-Koza, “UCP1: its involvement and utility in obesity,” International Journal of Obesity, vol. 32, no. 7, pp. S32–S38, 2008.
[40]
N. G. Barra, S. Reid, R. MacKenzie et al., “Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes,” Obesity, vol. 18, no. 8, pp. 1601–1607, 2010.
[41]
T. Christiansen, S. K. Paulsen, J. M. Bruun, S. B. Pedersen, and B. Richelsen, “Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: a 12-week randomized intervention study,” American Journal of Physiology, vol. 298, no. 4, pp. E824–E831, 2010.
[42]
L. S. Quinn, B. G. Anderson, L. Strait-Bodey, A. M. Stroud, and J. M. Argués, “Oversecretion of interleukin-15 from skeletal muscle reduces adiposity,” American Journal of Physiology, vol. 296, no. 1, pp. E191–E202, 2009.
[43]
V. Almendro, N. Carbó, S. Busquets et al., “Interleukin-15 decreases lipid intestinal absorption,” International Journal of Molecular Medicine, vol. 15, no. 6, pp. 963–967, 2005.
[44]
N. Carbó, J. López-Soriano, P. Costelli et al., “Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats,” British Journal of Cancer, vol. 83, no. 4, pp. 526–531, 2000.
[45]
B. Alvarez, N. Carbó, J. López-Soriano et al., “Effects of interleukin-15 (IL-15) on adipose tissue mass in rodent obesity models: evidence for direct IL-15 action on adipose tissue,” Biochimica et Biophysica Acta, vol. 1570, no. 1, pp. 33–37, 2002.
[46]
K. M. Ajuwon and M. E. Spurlock, “Direct regulation of lipolysis by interleukin-15 in primary pig adipocytes,” American Journal of Physiology, vol. 287, no. 3, pp. R608–R611, 2004.
[47]
V. Almendro, G. Fuster, E. Ametller et al., “Interleukin-15 increases calcineurin expression in 3T3-L1 cells: possible involvement on in vivo adipocyte differentiation,” International Journal of Molecular Medicine, vol. 24, no. 4, pp. 453–458, 2009.
[48]
T. Sugiura, M. Harigai, Y. Kawaguchi et al., “Increased IL-15 production of muscle cells in polymyositis and dermatomyositis,” International Immunology, vol. 14, no. 8, pp. 917–924, 2002.
[49]
A. R. Nielsen, R. Mounier, P. Plomgaard, et al., “Expression of interleukin-15 in human skeletal muscle—effect of exercise and muscle fibre type composition,” Journal of Physiology, vol. 584, no. 1, pp. 305–312, 2007.
[50]
P. L. Lollini, G. Palmieri, C. De Giovanni et al., “Expression of interleukin 15 (IL-15) in human rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma,” International Journal of Cancer, vol. 71, no. 5, pp. 732–736, 1997.
[51]
T. Stegall and K. A. Krolick, “Myocytes respond to both interleukin-4 and interferon-γ: cytokine responsiveness with the potential to influence the severity and course of experimental myasthenia gravis,” Clinical Immunology, vol. 94, no. 2, pp. 133–139, 2000.
[52]
D. C. Nieman, J. M. Davis, D. A. Henson et al., “Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine levels after a 3-h run,” Journal of Applied Physiology, vol. 94, no. 5, pp. 1917–1925, 2003.
[53]
D. C. Nieman, J. M. Davis, V. A. Brown et al., “Influence of carbohydrate ingestion on immune changes after 2 h of intensive resistance training,” Journal of Applied Physiology, vol. 96, no. 4, pp. 1292–1298, 2004.
[54]
A. R. Nielsen and B. K. Pedersen, “The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15,” Applied Physiology, Nutrition and Metabolism, vol. 32, no. 5, pp. 833–839, 2007.
[55]
K. Ostrowski, C. Hermann, A. Bangash, P. Schjerling, J. N. Nielsen, and B. K. Pedersen, “A trauma-like elevation of plasma cytokines in humans in response to treadmill running,” Journal of Physiology, vol. 513, no. 3, pp. 889–894, 1998.
[56]
H. Andersson, S. K. B？hn, T. Raastad, G. Paulsen, R. Blomhoff, and F. Kadi, “Differences in the inflammatory plasma cytokine response following two elite female soccer games separated by a 72-h recovery,” Scandinavian Journal of Medicine and Science in Sports, vol. 20, no. 5, pp. 740–747, 2010.
[57]
J. Prestes, G. Shiguemoto, J. P. Botero et al., “Effects of resistance training on resistin, leptin, cytokines, and muscle force in elderly post-menopausal women,” Journal of Sports Sciences, vol. 27, no. 14, pp. 1607–1615, 2009.
[58]
K. M. Beavers, F. C. Hsu, S. Isom et al., “Long-term physical activity and inflammatory biomarkers in older adults,” Medicine & Science in Sports & Exercise, vol. 42, no. 12, pp. 2189–2196, 2010.
[59]
J. Hansen, C. Brandt, A. R. Nielsen et al., “Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine,” Endocrinology, vol. 152, no. 1, pp. 164–171, 2011.
[60]
C. P. Lambert, M. G. Flynn, D. H. Sullivan, and W. J. Evans, “Effects of megestrol acetate on circulating interleukin-15 and interleukin-18 concentrations in healthy elderly men,” The Journals of Gerontology Series A, vol. 59, no. 8, pp. 855–858, 2004.
[61]
S. Raichur, P. Lau, B. Staels, and G. E. O. Muscat, “Retinoid-related orphan receptor γ regulates several genes that control metabolism in skeletal muscle cells: links to modulation of reactive oxygen species production,” Journal of Molecular Endocrinology, vol. 39, no. 1-2, pp. 29–44, 2007.
[62]
C. M. Kotz, C. J. Billington, and A. S. Levine, “Obesity and aging,” Clinics in Geriatric Medicine, vol. 15, no. 2, pp. 391–312, 1999.
[63]
E. E. Pistilli, P. M. Siu, and S. E. Alway, “Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy,” American Journal of Physiology, vol. 292, no. 4, pp. C1298–C1304, 2007.
[64]
J. S. Pattison, L. C. Folk, R. W. Madsen, and F. W. Booth, “Selected contribution: identification of differentially expressed genes between young and old rat soleus muscle during recovery from immobilization-induced atrophy,” Journal of Applied Physiology, vol. 95, no. 5, pp. 2171–2179, 2003.
[65]
E. Marzetti, C. S. Carter, S. E. Wohlgemuth et al., “Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction,” Mechanisms of Ageing and Development, vol. 130, no. 4, pp. 272–280, 2009.
[66]
S. Gangemi, G. Basile, D. Monti et al., “Age-related modifications in circulating IL-15 levels in humans,” Mediators of Inflammation, vol. 2005, no. 4, pp. 245–247, 2005.
[67]
J. Eisenman, M. Ahdieh, C. Beers et al., “Interleukin-15 interactions with interleukin-15 receptor complexes: characterization and species specificity,” Cytokine, vol. 20, no. 3, pp. 121–129, 2002.
[68]
Y. He, X. Wu, R. S. Khan et al., “IL-15 receptor deletion results in circadian changes of locomotor and metabolic activity,” Journal of Molecular Neuroscience, vol. 41, no. 2, pp. 315–321, 2010.
[69]
D. M. Anderson, S. Kumaki, M. Ahdieh et al., “Functional characterization of the human interleukin-15 receptor α chain and close linkage of IL15RA and IL2RA genes,” Journal of Biological Chemistry, vol. 270, no. 50, pp. 29862–29869, 1995.
[70]
J. Hager, C. Dina, S. Francke et al., “A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10,” Nature Genetics, vol. 20, no. 3, pp. 304–308, 1998.
[71]
R. S. Lindsay, S. Kobes, W. C. Knowler, P. H. Bennett, and R. L. Hanson, “Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians,” Diabetes, vol. 50, no. 12, pp. 2850–2857, 2001.
[72]
V. Budagian, E. Bulanova, Z. Orinska et al., “Natural soluble interleukin-15Rα is generated by cleavage that involves the tumor necrosis factor-α-converting enzyme (TACE/ADAM17),” Journal of Biological Chemistry, vol. 279, no. 39, pp. 40368–40375, 2004.
[73]
A. Monroy, S. Kamath, A. O. Chavez et al., “Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans,” Diabetologia, vol. 52, no. 10, pp. 2169–2181, 2009.
[74]
M. Serino, R. Menghini, L. Fiorentino et al., “Mice heterozygous for tumor necrosis factor-α converting enzyme are protected from obesity-induced insulin resistance and diabetes,” Diabetes, vol. 56, no. 10, pp. 2541–2546, 2007.
[75]
T. Kubota, R. A. Brown, J. Fang, and J. M. Krueger, “Interleukin-15 and interleukin-2 enhance non-REM sleep in rabbits,” American Journal of Physiology, vol. 281, no. 3, pp. R1004–R1012, 2001.
[76]
X. Wu, W. Pan, Y. He, H. Hsuchou, and A. J. Kastin, “Cerebral interleukin-15 shows upregulation and beneficial effects in experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 223, no. 1-2, pp. 65–72, 2010.
