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Animal Models

Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain

International Journal of Obesity volume 40, pages 844–851 (2016)Cite this article

Subjects

Abstract

Background:

Monocyte chemoattractant protein 1 (MCP-1) is known to be an important chemokine for macrophage recruitment. Thus, targeting MCP-1 may prevent the perturbations associated with macrophage-induced inflammation in adipose tissue. However, inconsistencies in the available animal literature have questioned the role of this chemokine in this process. The purpose of this study was to examine the role of MCP-1 on obesity-related pathologies.

Methods:

Wild-type and MCP-1-deficient mice on an friend virus B NIH (FVB/N) background were assigned to either low-fat diet or high-fat diet (HFD) treatment for a period of 16 weeks. Body weight and body composition were measured weekly and monthly, respectively. Fasting blood glucose and insulin, and glucose tolerance were measured at 16 weeks. Macrophages, T-cell markers, inflammatory mediators and markers of fibrosis were examined in the adipose tissue at the time of killing the mice.

Results:

As expected, HFD increased adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysfunction (impaired glucose metabolism and insulin resistance) macrophage number (CD11b+F480+ cells, and gene expression of EMR1 and CD11c), T-cell markers (gene expression of CD4 and CD8), inflammatory mediators (pNFκB and pJNK, and mRNA expression of MCP-1, CCL5, C-X-C motif chemokine-14, tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) and fibrosis (expression of IL-10, IL-13, TGF-β and matrix metalloproteinase-2 (MMP2); P<0.05). However, contrary to our hypothesis, MCP-1 deficiency exacerbated many of these responses resulting in a further increase in adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysregulation, macrophage markers (EMR1), inflammatory cell infiltration and fibrosis (formation of type I and III collagens, mRNA expression of IL-10 and MMP2; P<0.05).

Conclusions:

These data suggest that MCP-1 may be a necessary component of the inflammatory response required for adipose tissue protection, remodeling and healthy expansion in the FVB/N strain in response to HFD feedings.

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References

  1. Roberts DL, Dive C, Renehan AG . Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010; 61: 301–316.

    Article  CAS  Google Scholar 

  2. Basen-Engquist K, Chang M . Obesity and cancer risk: recent review and evidence. Curr Oncol Rep 2011; 13: 71–76.

    Article  Google Scholar 

  3. Kahn SE, Hull RL, Utzschneider KM . Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–846.

    Article  CAS  Google Scholar 

  4. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

    Article  Google Scholar 

  5. Olefsky JM, Glass CK . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246.

    Article  CAS  Google Scholar 

  6. Ungefroren H, Gieseler F, Fliedner S, Lehnert H . Obesity and cancer. Horm Mol Biol Clin Investig 2015; 21: 5–15.

    CAS  PubMed  Google Scholar 

  7. Fox KR, Hillsdon M . Physical activity and obesity. Obes Rev 2007; 8 (Suppl 1): 115–121.

    Article  Google Scholar 

  8. Wareham NJ, van Sluijs EM, Ekelund U . Physical activity and obesity prevention: a review of the current evidence. Proc Nutr Soc 2005; 64: 229–247.

    Article  Google Scholar 

  9. Lemmens VE, Oenema A, Klepp KI, Henriksen HB, Brug J . A systematic review of the evidence regarding efficacy of obesity prevention interventions among adults. Obes Rev 2008; 9: 446–455.

    Article  CAS  Google Scholar 

  10. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–1808.

    Article  CAS  Google Scholar 

  11. Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR . Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008; 57: 3239–3246.

    Article  CAS  Google Scholar 

  12. Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.

    Article  CAS  Google Scholar 

  13. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116–1120.

    Article  CAS  Google Scholar 

  14. Landgraf K, Rockstroh D, Wagner IV, Weise S, Tauscher R, Schwartze JT et al. Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children. Diabetes 2015; 64: 1249–1261.

    Article  CAS  Google Scholar 

  15. Bremer AA, Devaraj S, Afify A, Jialal I . Adipose tissue dysregulation in patients with metabolic syndrome. J Clin Endocrinol Metab 2011; 96: E1782–E1788.

    Article  CAS  Google Scholar 

  16. Arner E, Mejhert N, Kulyte A, Balwierz PJ, Pachkov M, Cormont M et al. Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 2012; 61: 1986–1993.

    Article  CAS  Google Scholar 

  17. Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab 2014; 19: 162–171.

    Article  CAS  Google Scholar 

  18. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006; 281: 26602–26614.

    Article  CAS  Google Scholar 

  19. Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ et al. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007; 56: 2242–2250.

    Article  CAS  Google Scholar 

  20. Galastri S, Zamara E, Milani S, Novo E, Provenzano A, Delogu W et al. Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis. Clin Sci (Lond) 2012; 123: 459–471.

    Article  CAS  Google Scholar 

  21. Enos RT, Davis JM, Velazquez KT, McClellan JL, Day SD, Carnevale KA et al. Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters. J Lipid Res 2013; 54: 152–163.

    Article  CAS  Google Scholar 

  22. Enos RT, Velazquez KT, Murphy EA . Insight into the impact of dietary saturated fat on tissue-specific cellular processes underlying obesity-related diseases. J Nutr Biochem 2014; 25: 600–612.

    Article  CAS  Google Scholar 

  23. Grotto D, Zied E . The Standard American Diet and its relationship to the health status of Americans. Nutr Clin Pract 2010; 25: 603–612.

    Article  Google Scholar 

  24. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  25. Schneider CA, Rasband WS, Eliceiri KW . NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9: 671–675.

    Article  CAS  Google Scholar 

  26. Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.

    Article  CAS  Google Scholar 

  27. Enos RT, Velazquez KT, McClellan JL, Cranford TL, Walla MD, Murphy EA . Reducing the dietary omega-6:omega-3 utilizing alpha-linolenic acid; not a sufficient therapy for attenuating high-fat-diet-induced obesity development nor related detrimental metabolic and adipose tissue inflammatory outcomes. PLoS One 2014; 9: e94897.

    Article  Google Scholar 

  28. Enos RT, Velazquez KT, McClellan JL, Cranford TL, Walla MD, Murphy EA . Lowering the dietary omega-6: omega-3 does not hinder nonalcoholic fatty-liver disease development in a murine model. Nutr Res 2015; 35: 449–459.

    Article  CAS  Google Scholar 

  29. Kim DH, Gutierrez-Aguilar R, Kim HJ, Woods SC, Seeley RJ . Increased adipose tissue hypoxia and capacity for angiogenesis and inflammation in young diet-sensitive C57 mice compared with diet-resistant FVB mice. Int J Obes (Lond) 2013; 37: 853–860.

    Article  CAS  Google Scholar 

  30. Le Lay S, Boucher J, Rey A, Castan-Laurell I, Krief S, Ferre P et al. Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem Biophys Res Commun 2001; 289: 564–567.

    Article  CAS  Google Scholar 

  31. Hu CC, Qing K, Chen Y . Diet-induced changes in stearoyl-CoA desaturase 1 expression in obesity-prone and -resistant mice. Obes Res 2004; 12: 1264–1270.

    Article  CAS  Google Scholar 

  32. Metlakunta AS, Sahu M, Sahu A . Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. Endocrinology 2008; 149: 1121–1128.

    Article  CAS  Google Scholar 

  33. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494–1505.

    Article  CAS  Google Scholar 

  34. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116: 115–124.

    Article  CAS  Google Scholar 

  35. Chow FY, Nikolic-Paterson DJ, Ma FY, Ozols E, Rollins BJ, Tesch GH . Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice. Diabetologia 2007; 50: 471–480.

    Article  CAS  Google Scholar 

  36. Chen A, Mumick S, Zhang C, Lamb J, Dai H, Weingarth D et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 2005; 13: 1311–1320.

    Article  CAS  Google Scholar 

  37. Kirk EA, Sagawa ZK, McDonald TO, O'Brien KD, Heinecke JW . Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 2008; 57: 1254–1261.

    Article  CAS  Google Scholar 

  38. Zimmermann HW, Tacke F . Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets 2011; 10: 509–536.

    Article  CAS  Google Scholar 

  39. Wernstedt Asterholm I, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20: 103–118.

    Article  CAS  Google Scholar 

  40. Hemmrich K, Thomas GP, Abberton KM, Thompson EW, Rophael JA, Penington AJ et al. Monocyte chemoattractant protein-1 and nitric oxide promote adipogenesis in a model that mimics obesity. Obesity 2007; 15: 2951–2957.

    Article  CAS  Google Scholar 

  41. Younce C, Kolattukudy P . MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy. Cell Physiol Biochem 2012; 30: 307–320.

    Article  CAS  Google Scholar 

  42. Sartipy P, Loskutoff DJ . Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100: 7265–7270.

    Article  CAS  Google Scholar 

  43. Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD . Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001; 175: 81–92.

    Article  CAS  Google Scholar 

  44. Kim D, Kim J, Yoon JH, Ghim J, Yea K, Song P et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 2014; 57: 1456–1465.

    Article  CAS  Google Scholar 

  45. Chatterjee P, Seal S, Mukherjee S, Kundu R, Mukherjee S, Ray S et al. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J Biol Chem 2013; 288: 28324–28330.

    Article  CAS  Google Scholar 

  46. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914–920.

    Article  CAS  Google Scholar 

  47. Xiao L, Yang X, Lin Y, Li S, Jiang J, Qian S et al. Large adipocytes function as antigen presenting cells to activate CD4+ T cells via up-regulating MHCII in obesity. Int J Obes (Lond) 2015; e-pub ahead of print 7 August 2013; doi:10.1038/ijo.2015.145.

    Article  Google Scholar 

  48. Carter CP, Howles PN, Hui DY . Genetic variation in cholesterol absorption efficiency among inbred strains of mice. J Nutr 1997; 127: 1344–1348.

    Article  CAS  Google Scholar 

  49. Keelan M, Hui DY, Wild G, Clandinin MT, Thomson AB . Variability of the intestinal uptake of lipids is genetically determined in mice. Lipids 2000; 35: 833–837.

    Article  CAS  Google Scholar 

  50. Fearnside JF, Dumas ME, Rothwell AR, Wilder SP, Cloarec O, Toye A et al. Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice. PloS One 2008; 3: e1668.

    Article  Google Scholar 

  51. Montgomery MK, Hallahan NL, Brown SH, Liu M, Mitchell TW, Cooney GJ et al. Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 2013; 56: 1129–1139.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institutes of Health (F31CA183458 to T.L.C. and R21CA167058, R21CA175636 & K01AT007824 to E.A.M.) and the University of South Carolina (Advanced Support Programs for Innovative Research Excellence (ASPIRE) to E.A.M.).

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Authors and Affiliations

  1. Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA

    T L Cranford, R T Enos, K T Velázquez, J L McClellan, U P Singh, M Nagarkatti, P S Nagarkatti & E A Murphy

  2. Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA

    J M Davis

  3. Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA

    C M Robinson

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  1. T L Cranford
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Correspondence to E A Murphy.

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Cranford, T., Enos, R., Velázquez, K. et al. Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain. Int J Obes 40, 844–851 (2016). https://doi.org/10.1038/ijo.2015.244

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