Abstract
Animal studies have demonstrated that the ratio of M1 (M1Φ) to M2 (M2Φ) macrophage-specific gene expression in adipose tissue (AT) may be altered by chronic exercise; however, whether macrophage polarization is induced under these conditions has not yet been reported. Therefore, this study aimed to investigate the effect of chronic exercise on M1Φ/M2Φ polarization in the AT of high-fat diet (HFD)-induced obese mice. Exercise-induced differences in M1Φ/M2Φ polarization were verified via an exercise intensity study (EIS) in which different levels of exercise intensity were evaluated. Obesity was induced in male C57BL/6 J mice by feeding them with an HFD for 6 weeks. The study consisted of four groups: control group (CON), HFD-fed group (HFD), HFD-fed with exercise group (HFD + EXE), dietary conversion from HFD to normal diet (ND) group (DC), and dietary conversion from HFD to ND group (DC + EXE). For EIS, the HFD + EXE group was divided into three subgroups: low- (LI), mid- (MI), and high- (HI) intensity exercise. The total intervention period was 8 weeks. M1Φ/M2Φ polarization was confirmed by flow cytometry. M2Φ polarization in the AT of obese mice was significantly higher in HFD + EXE mice than in HFD mice, despite the HFD intake. In the EIS, M2Φ polarization was most pronounced in HFD + EXE-HI mice than in HFD mice. It can be proposed that the enhanced insulin resistance and inflammation by obesity can be improved by the increase of M2Φ polarization which is achieved by relatively high-intensity exercise.
Similar content being viewed by others
References
Baek K-W (2018) Effects of a single of bout exercise on the macrophage phenotypic ratio in the adipose tissue of high-fat diet-induced obese mice. Exerc Sci 27:232–243. https://doi.org/10.15857/ksep.2018.27.3.232
Baek K-W, Gim J-A, Park J-J (2018) Regular moderate aerobic exercise improves high-fat diet-induced nonalcoholic fatty liver disease via monoacylglycerol O-acyltransferase 1 pathway suppression. J Sport Health Sci. https://doi.org/10.1016/j.jshs.2018.09.001
Baek KW, Cha HJ, Ock MS, Kim HS, Gim JA, Park JJ (2018) Effects of regular-moderate exercise on high-fat diet-induced intramyocellular lipid accumulation in the soleus muscle of Sprague-Dawley rats. J Exerc Rehabil 14:32–38. https://doi.org/10.12965/jer.1835166.583
Blundell JE, King NA (1999) Physical activity and regulation of food intake: current evidence. Med Sci Sports Exerc 31:S573–S583. https://doi.org/10.1097/00005768-199911001-00015
Bruun JM, Helge JW, Richelsen B, Stallknecht B (2006) 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 290:E961–E967. https://doi.org/10.1152/ajpendo.00506.2005
Deiuliis J, Shah Z, Shah N, Needleman B, Mikami D, Narula V, Perry K, Hazey J, Kampfrath T, Kollengode M, Sun Q, Satoskar AR, Lumeng C, Moffatt-Bruce S, Rajagopalan S (2011) Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6:e16376. https://doi.org/10.1371/journal.pone.0016376
Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO (1999) ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion. J Immunol 163:668–674
Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582. https://doi.org/10.2337/db08-1475
Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA (2011) The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11:607–615. https://doi.org/10.1038/nri3041
Hawley JA (2004) Exercise as a therapeutic intervention for the prevention and treatment of insulin resistance. Diabetes Metab Res Rev 20:383–393. https://doi.org/10.1002/dmrr.505
Heikkinen S, Argmann CA, Champy MF, Auwerx J (2007) Evaluation of glucose homeostasis. Curr Protoc Mol Biol chapter 29:unit 29B 23. https://doi.org/10.1002/0471142727.mb29b03s77
Ivy JL (1997) Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus. Sports Med 24:321–336. https://doi.org/10.2165/00007256-199724050-00004
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505. https://doi.org/10.1172/JCI26498
Kawanishi N, Yano H, Yokogawa Y, Suzuki K (2010) Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev 16:105–118
Kelly B, O'Neill LA (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25:771–784. https://doi.org/10.1038/cr.2015.68
Kempen KP, Saris WH, Westerterp KR (1995) Energy balance during an 8-wk energy-restricted diet with and without exercise in obese women. Am J Clin Nutr 62:722–729. https://doi.org/10.1093/ajcn/62.4.722
King N, Lluch A, Stubbs R, Blundell J (1997) High dose exercise does not increase hunger or energy intake in free living males. Eur J Clin Nutr 51:478–483. https://doi.org/10.1038/sj.ejcn.1600432
Lee BC, Kim MS, Pae M, Yamamoto Y, Eberle D, Shimada T, Kamei N, Park HS, Sasorith S, Woo JR, You J, Mosher W, Brady HJ, Shoelson SE, Lee J (2016) Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 23:685–698. https://doi.org/10.1016/j.cmet.2016.03.002
Levak-Frank S, Radner H, Walsh A, Stollberger R, Knipping G, Hoefler G, Sattler W, Weinstock PH, Breslow JL, Zechner R (1995) Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest 96:976–986. https://doi.org/10.1172/JCI118145
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184. https://doi.org/10.1172/JCI29881
Lyngso D, Simonsen L, Bulow J (2002) Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise. J Physiol 543:373–378. https://doi.org/10.1113/jphysiol.2002.019380
Lyngso D, Simonsen L, Bulow J (2002) Metabolic effects of interleukin-6 in human splanchnic and adipose tissue. J Physiol 543:379–386. https://doi.org/10.1113/jphysiol.2002.021022
Makki K, Froguel P, Wolowczuk I (2013) Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013:139239. https://doi.org/10.1155/2013/139239
Mela D (2005) Food, diet and obesity. Elsevier, Amsterdam
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920. https://doi.org/10.1038/nm.1964
Oliveira AG, Araujo TG, Carvalho BM, Guadagnini D, Rocha GZ, Bagarolli RA, Carvalheira JB, Saad MJ (2013) Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats. Obesity (Silver Spring) 21:2545–2556. https://doi.org/10.1002/oby.20402
Pomerleau M, Imbeault P, Parker T, Doucet E (2004) Effects of exercise intensity on food intake and appetite in women. Am J Clin Nutr 80:1230–1236. https://doi.org/10.1093/ajcn/80.5.1230
Prentice AM, Jebb SA (2003) Fast foods, energy density and obesity: a possible mechanistic link. Obes Rev 4:187–194. https://doi.org/10.1046/j.1467-789x.2003.00117.x
Racette SB, Schoeller DA, Kushner RF, Neil KM, Herling-Iaffaldano K (1995) Effects of aerobic exercise and dietary carbohydrate on energy expenditure and body composition during weight reduction in obese women. Am J Clin Nutr 61:486–494. https://doi.org/10.1093/ajcn/61.3.486
Strasser B (2013) Physical activity in obesity and metabolic syndrome. Ann N Y Acad Sci 1281:141–159. https://doi.org/10.1111/j.1749-6632.2012.06785.x
van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005–3010. https://doi.org/10.1210/jc.2002-021687
Wadden TA, Stunkard AJ (2002) Handbook of obesity treatment. Guilford Press, New York
Warburton DE, Nicol CW, Bredin SS (2006) Health benefits of physical activity: the evidence. CMAJ 174:801–809. https://doi.org/10.1503/cmaj.051351
Weinstein AR, Sesso HD, Lee IM, Cook NR, Manson JE, Buring JE, Gaziano JM (2004) Relationship of physical activity vs body mass index with type 2 diabetes in women. JAMA 292:1188–1194. https://doi.org/10.1001/jama.292.10.1188
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808. https://doi.org/10.1172/JCI19246
Winchester L, Veeranki S, Givvimani S, Tyagi SC (2014) Exercise mitigates the adverse effects of hyperhomocysteinemia on macrophages, MMP-9, skeletal muscle, and white adipocytes. Can J Physiol Pharmacol 92:575–582. https://doi.org/10.1139/cjpp-2014-0059
Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (2005) ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow. Blood 106:584–592. https://doi.org/10.1182/blood-2004-12-4942
Funding
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2018R1A6A3A01011328).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use and Committee of Pusan National University (approval number, PNU-2017-1669).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Key Points
• Regular chronic exercise downregulates Icam-1 & Tnf in adipose tissue of obese mice
• Regular chronic exercise upregulates Arg1 in adipose tissue of obese mice
• It increases M2 macrophage polarization in adipose tissue of obese mice
• High-intensity exercise may increase M2 macrophage polarization in adipose tissue
Rights and permissions
About this article
Cite this article
Baek, KW., Lee, DI., Kang, S.A. et al. Differences in macrophage polarization in the adipose tissue of obese mice under various levels of exercise intensity. J Physiol Biochem 76, 159–168 (2020). https://doi.org/10.1007/s13105-020-00731-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-020-00731-7