Exercise Training Decreases Adipose Tissue Inflammation in Cachectic Rats

Abstract

Bearing in mind that cancer cachexia is associated with chronic systemic inflammation and that endurance training has been adopted as a nonpharmacological anti-inflammatory strategy, we examined the effect of 8 weeks of moderate intensity exercise upon the balance of anti- and pro-inflammatory cytokines in 2 different depots of white adipose tissue in cachectic tumour-bearing (Walker-256 carcinosarcoma) rats. Animals were assigned to a sedentary control (SC), sedentary tumour-bearing (ST), sedentary pair-fed (SPF) or exercise control (EC), exercise tumour-bearing (ET), and exercise pair-fed (EPF) group. Trained rats ran on a treadmill (60% VO₂max) 60 min/day, 5 days/week, for 8 weeks. The retroperitoneal (RPAT) and mesenteric (MEAT) adipose pads were excised and the mRNA (RT-PCR) and protein (ELISA) expression of IL-1β, IL-6, TNF-α, and IL-10 were evaluated. The number of infiltrating monocytes in the adipose tissue was increased in cachectic rats. TNF-α mRNA in MEAT was increased in the cachectic animals (p<0.05) in relation to SC. RPAT protein expression of all studied cytokines was increased in cachectic animals in relation to SC and SPF (p<0.05). In this pad, IL-10/TNF-α ratio was reduced in the cachectic animals in comparison with SC (p<0.05) indicating inflammation. Exercise training improved IL-10/TNF-α ratio and induced a reduction of the infiltrating monocytes both in MEAT and RPAT (p<0.05), when compared with ST. We conclude that cachexia is associated with inflammation of white adipose tissue and that exercise training prevents this effect in the MEAT, and partially in RPAT.

Key words

cancer-cachexia - adipose tissue - cytokines - exercise training - inflammation

• References

• 1 Argilés J, Alvarez B, López-Soriano F. The metabolic basis of cancer cachexia. Med Res Rev 1997; 17: 477-498
• 2 Tisdale M. Wasting in cancer. J Nutr 1999; 129 (Suppl) 243S-246S
• 3 Stewart GD, Skipworth RJ, Fearon KC. Cancer cachexia and fatigue. Clin Med 2006; 6: 140-143
• 4 Argilés JM, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, Muscaritoli M, Baracos VE. Consensus on cachexia definitions. J Am Med Dir Assoc 2010; 11: 229-230
• 5 Baldwin C. Nutritional support for malnourished patients with cancer. Curr Opin Support Palliat Care 2011; 5: 29-36
• 6 Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, Macdonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011; 12: 489-495
• 7 Lira FS, Rosa JC, Zanchi NE, Yamashita AS, Lopes RD, Lopes AC, Batista Jr ML, Seelaender M. Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise. Cell Biochem Funct 2009; 27: 71-75
• 8 Mracek T, Stephens NA, Gao D, Bao Y, Ross JA, Rydén M, Arner P, Trayhurn P, Fearon KC, Bing C. Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients. Br J Cancer 2011; 104: 441-447
• 9 Bing C, Trayhurn P. Regulation of adipose tissue metabolism in cancer cachexia. Curr Opin Clin Nutr Metab Care 2008; 11: 201-217
• 10 Figueras M, Busquets S, Carbó N, Almendro V, Argilés J, López-Soriano F. Cancer cachexia results in an increase in TNF-alpha receptor gene expression in both skeletal muscle and adipose tissue. Int J Oncol 2005; 27: 855-860
• 11 Machado AP, Costa Rosa LF, Seelaender MC. Adipose tissue in Walker 256 tumour-induced cachexia: possible association between decreased leptin concentration and mononuclear cell infiltration. Cell Tissue Res 2004; 318: 503-514
• 12 Costa Rosa LF. Exercise as a Time-conditioning Effector in Chronic Disease: a Complementary Treatment Strategy. Evid Based Complement Alternat Med 2004; 1: 63-70
• 13 Lira FS, Rosa JC, Pimentel GD, Tarini VA, Arida RM, Faloppa F, Alves ES, do Nascimento CO, Oyama LM, Seelaender M, de Mello MT, Santos RV. Inflammation and adipose tissue: effects of progressive load training in rats. Lipids Health Dis 2010; 9: 109
• 14 Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005; 98: 1154-1162
• 15 Rubin DA, Hackney AC. Inflammatory cytokines and metabolic risk factors during growth and maturation: influence of physical activity. Ed Sport Sci 2010; 55: 43-55
• 16 Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta 2010; 411: 785-793
• 17 Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK, Kim HJ, Kim DJ, Lee KW. Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. J Clin Biochem Nutr 2008; 19: 371-375
• 18 Lira FS, Rosa JC, Yamashita AS, Koyama CH, Batista Jr ML, Seelaender M. Endurance training induces depot-specific changes in IL-10/TNF-alpha ratio in rat adipose tissue. Cytokine 2009; 45: 80-85
• 19 Eliakim A, Nemet D. Exercise training, physical fitness and the growth hormone-insulin-like growth factor-1 axis and cytokine balance. Med Sport Sci 2010; 55: 128-140
• 20 Glover EI, Phillips SM. Resistance exercise and appropriate nutrition to counteract muscle wasting and promote muscle hypertrophy. Curr Opin Clin Nutr Metab Care 2010; 13: 630-634
• 21 Peluso G, Nicolai R, Reda E, Bennati P, Barbarisi P, Calvani M. Cancer And Anticancer Therapy-Induced Modifications On Metabolism Mediated By Carnitine System. J Cell Physiol 2000; 182: 339-350
• 22 Lira FS, Tavares FL, Yamashita AS, Koyama CH, Alves MJ, Caperuto EC, Batista Jr ML, Seelaender M. Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats. Cell Biochem Funct 2008; 26: 701-708
• 23 Bacurau RF, Belmonte MA, Seelaender MC, Costa Rosa LF. Effect of a moderate intensity exercise training protocol on the metabolism of macrophages and lymphocytes of tumour-bearing rats. Cell Biochem Funct 2000; 18: 249-258
• 24 Lira FS, Yamashita A, Carnevali Jr LC, Gonçalves DC, Lima WP, Rosa JC, Caperuto EC, Rosa LF, Seelaender M. Exercise training reduces PGE2 levels and induces recovery from steatosis in tumor-bearing rats. Horm Metab Res 2010; 42: 944-949
• 25 Leonidou L, Mouzaki A, Michalaki M, DeLastic AL, Kyriazopoulou V, Bassaris HP, Gogos CA. Cytokine production and hospital mortality in patients with sepsis-induced stress hyperglycemia. J Infect 2007; 55: 340-346
• 26 Batista Jr ML, Rosa JC, Lopes RD, Lira FS, Martins Jr E, Yamashita AS, Brum PC, Lancha Jr AH, Lopes AC, Seelaender M. Exercise training changes IL-10/TNF-alpha ratio in the skeletal muscle of post-MI rats. Cytokine 2010; 49: 102-108
• 27 Lira FS, Rosa JC, Dos Santos RV, Venancio DP, Carnier J, Sanches Pde L, do Nascimento CM, de Piano A, Tock L, Tufik S, de Mello MT, Dâmaso AR, Oyama LM. Visceral fat decreased by long-term interdisciplinary lifestyle therapy correlated positively with interleukin-6 and tumor necrosis factor-α and negatively with adiponectin levels in obese adolescents. Metabolism 2011; 60: 359-365
• 28 Mccarthy H, Mckibbin P, Perkins A, Linton E, Williams G. Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats. Am J Physiol 1993; 264: E638-E643
• 29 Seelaender MC, Nascimento CM, Curi R, Willians JF. Studies on the lipid metabolism of Walker 256 tumour-bearing rats during the development of cancer cachexia. Biochem Mol Biol Int 1996; 39: 1037-1047
• 30 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-918
• 31 Ploeger HE, Takken T, de Greef MH, Timmons BW. The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc Immunol Rev 2009; 15: 6-41
• 32 Salomão EM, Toneto AT, Silva GO, Gomes-Marcondes MC. Physical exercise and a leucine-rich diet modulate the muscle protein metabolism in Walker tumor-bearing rats. Nutr Cancer 2010; 62: 1095-1104
• 33 Deuster PA, Morrison SD, Ahrens RA. Endurance exercise modifies cachexia of tumor growth in rats. Med Sci Sports Exerc 1985; 17: 385-392
• 34 Pond C. Paracrine relationships between adipose and lymphoid tissues: implications for the mechanism of HIV-associated adipose redistribution syndrome. Trends Immunol 2003; 24: 13-18
• 35 Kazantzis M, Seelaender MC. Cancer cachexia modifies the zonal distribution of lipid metabolism-related proteins in rat liver. Cell Tissue Res 2005; 321: 419-427
• 36 Silvério R, Laviano A, Fanelli FR, Seelaender ML. Carnitine induces recovery of liver lipid metabolism in cancer cachexia. Amino Acids 2011; Apr 5 [Epub ahead of print]
• 37 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004; 92: 347-355
• 38 Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, Gorkiewicz G, Tamilarasan KP, Kumari P, Trauner M, Zimmermann R, Vesely P, Haemmerle G, Zechner R, Hoefler G. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011; 333 (6039) 233-238
• 39 Malefyt R. Interleukin-10. In: Mire-Sluis A, Thorpe R. (eds.) Cytokines. 2^nd ed. Blanch Lane: Academic Press; 1999: 151-161
• 40 Moore K, O’garra A, De Waal Malefyt R, Vieira P, Mosmann T. Interleukin-10. Annu Rev Immunol 1993; 11: 165-190
• 41 Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, Giugliano D. Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab 2003; 88: 1055-1058
• 42 Daftarian P, Kumar A, Kryworuchko M, Diaz-Mitoma F. IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha. J Immunol 1996; 157: 12-20
• 43 Ebrahimi B, Tucker SL, Li D, Abbruzzese JL, Kurzrock R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 2004; 101: 2727-2736
• 44 Passoja A, Puijola I, Knuuttila M, Niemelä O, Karttunen R, Raunio T, Tervonen T. Serum levels of interleukin-10 and tumour necrosis factor-α in chronic periodontitis. J Clin Periodontol 2010; 37: 881-887
• 45 Amir O, Rogowski O, David M, Lahat N, Wolff R, Lewis BS. Circulating interleukin-10: association with higher mortality in systolic heart failure patients with elevated tumor necrosis factor-alpha. Isr Med Assoc J 2010; 12: 158-162
• 46 Gottschling-Zeller H, Birgel M, Röhrig K, Hauner H. Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator inhibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture. Metabolism 2000; 49: 666-671
• 47 Manigrasso MR, Ferroni P, Santilli F, Taraborelli T, Guagnano MT, Michetti N, Davì G. Association between circulating adiponectin and interleukin-10 levels in android obesity: effects of weight loss. J Clin Endocrinol Metab 2005; 90: 5876-5879
• 48 Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 1998; 83: 2907-2910
• 49 Trayhurn P, Beattie J. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001; 60: 329-339
• 50 Permana P, Menge C, Reaven P. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun 2006; 10: 507-514
• 51 Bruun J, Helge JW, Richelsen B, Stallknecht B. Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 2006; 290: E961-E967
• 52 Yang A, Chen H. Chronic exercise reduces adhesion molecules/iNOS expression and partially reverses vascular responsiveness in hypercholesterolemic rabbit aortae. Atherosclerosis 2003; 169: 11-17
• 53 Osório-Costa F, Rocha GZ, Dias MM, Carvalheira JB. Epidemiological and molecular mechanisms aspects linking obesity and cancer. Arq Bras Endocrinol Metabol 2009; 53: 213-226
• 54 Chennaoui M, Drogou C, Gomez-Merino D. Effects of physical training on IL-1beta, IL-6 and IL-1ra concentrations in various brain areas of the rat. Eur Cytokine Netw 2008; 19: 8-14
• 55 Packer N, Pervaiz N, Hoffman-Goetz L. Exerc Immunol Rev 2010; 16: 138-162
• 56 Negrao CE, Middlekauff HR. Adaptations in autonomic function during exercise training in heart failure. Heart Fail Rev 2008; 13: 51-60
• 57 Molfino A, Logorelli F, Citro G, Bertini G, Ramaccini C, Bollea MR, Rossi Fanelli F, Laviano A. Stimulation of the nicotine antiinflammatory pathway improves food intake and body composition in tumor-bearing rats. Nutr Cancer 2011; 63: 295-299
• 58 Laviano A, Inui A, Marks DL, Meguid MM, Pichard C, Rossi Fanelli F, Seelaender M. Neural control of the anorexia-cachexia syndrome. Am J Physiol Endocrinol Metab 2008; 295: E1000-E1008
• 59 Grossberg AJ, Scarlett JM, Marks DL. Hypothalamic mechanisms in cachexia. Physiol Behav 2010; 100: 478-489
• 60 Ropelle ER, Pauli JR, Zecchin KG, Ueno M, de Souza CT, Morari J, Faria MC, Velloso LA, Saad MJ, Carvalheira JB. A central role for neuronal adenosine 5′-monophosphate-activated protein kinase in cancer-induced anorexia. Endocrinology 2007; 148: 5220-5229
• 61 Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB, Febbraio MA. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol 2009; 94: 1153-1160
• 62 Lira FS, Yamashita AS, Rosa JC, Tavares FL, Caperuto E, Carnevali Jr LC, Pimentel GD, Santos RV, Batista Jr ML, Laviano A, Rossi-Fanelli F, Seelaender M. Hypothalamic inflammation is reversed by endurance training in anorectic-cachectic rats. Nutr Metab (Lond) 24 2011; 8: 60