Role of Heat Shock Proteins in Obesity and Type 2 Diabetes

  • Punit Kaur
  • Michael D. Reis
  • Glen R. Couchman
  • Samuel N. Forjuoh
  • John F. GreeneJr
  • Alexzander AseaEmail author
Part of the Heat Shock Proteins book series (HESP, volume 5)


Heat shock proteins (HSP) play an important role in human health and physiology and are known to function intracellularly as cytoprotection proteins by protecting cells against a wide variety of stressors, and extracellularly as chaperokines by stimulating the synthesis of pro-inflammatory cytokines, chemokines, and upregulates co-stimulatory molecule expression on antigen presenting cells, and enhancing natural killer (NK) cell-mediated migration and general anti-tumor responses. Obesity is known to be associated with raised serum inflammatory markers suggesting a state of heightened immune activation. The recent findings that antibody titers to several HSP are elevated in dyslipidaemic patients and individuals with established vascular disease, and that patients with Type 2 diabetes have reduced gene expression of Hsp72 which correlates with reduced insulin sensitivity point to an important role for HSP in obesity and Type 2 diabetes. This chapter briefly reviews recent advances in our understanding of the role of Hsp70 in obesity and Type 2 diabetes


BMI cancer cardiovascular diseases diabetes obesity weight 



body mass index


center for disease control


C-reactive protein


cardiovascular disease


fasting blood glucose


free fatty acids


glucose regulated proteins


heat shock factor


heat shock proteins


heat shock protein gene


heat shock protein family


insulin growth factor-1




c-jun N-terminal kinase


mitogen activated protein kinases


monocyte chemotactic protein-1


natural killer


tumor necrosis factor-alpha


World Health Organization



The authors thank the Proteomics Core Facility at Scott & White Hospital and Clinic. This work was supported in part by the National Institutes of Health grant RO1CA91889, institutional support from Scott & White Memorial Hospital and Clinic, Texas A&M University System Health Science Center College of Medicine, the Central Texas Veterans Health Administration and an Endowment from the Cain Foundation (to A. A).


  1. Arguin, H., Bouchard, D. R., Labonte, M., Carpentier, A., Ardilouze, J. L., Dionne, I. J. and Brochu, M. (2008) Correlation between the rate of weight loss and changes in body composition in obese postmenopausal women after 5 weeks: a pilot study. Appl Physiol Nutr Metab 33, 347–355.CrossRefPubMedGoogle Scholar
  2. Asea, A. (2005a) Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 11, 34–45.PubMedGoogle Scholar
  3. Asea, A. (2005b) Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 11, 34–45.PubMedGoogle Scholar
  4. Asea, A. (2008a) Heat shock proteins and toll-like receptors. Handb Exp Pharmacol 183, 111–127.CrossRefPubMedGoogle Scholar
  5. Asea, A. (2008b) Hsp70: a chaperokine. Novartis Found Symp 291, 173–179; discussion 179–183, 221–174.CrossRefPubMedGoogle Scholar
  6. Asea, A. and DeMaio, A. (2007) Heat Shock Proteins: Potent Mediators of Inflammation and Immunity, Vol. 1. Springer, Dordrecht, The Netherlands.Google Scholar
  7. Asea, A., Kraeft, S. K., Kurt-Jones, E. A., Stevenson, M. A., Chen, L. B., Finberg, R. W., Koo, G. C. and Calderwood, S. K. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6, 435–442.CrossRefPubMedGoogle Scholar
  8. Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Bare, O., Auron, P. E., Stevenson, M. A. and Calderwood, S. K. (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277, 15028–15034.CrossRefPubMedGoogle Scholar
  9. Atalay, M., Oksala, N. K., Laaksonen, D. E., Khanna, S., Nakao, C., Lappalainen, J., Roy, S., Hanninen, O. and Sen, C. K. (2004) Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 97, 605–611.CrossRefPubMedGoogle Scholar
  10. Bausero, M. A., Gastpar, R., Multhoff, G. and Asea, A. (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175, 2900–2912.PubMedGoogle Scholar
  11. Bruce, C. R., Carey, A. L., Hawley, J. A. and Febbraio, M. A. (2003) Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52, 2338–2345.CrossRefPubMedGoogle Scholar
  12. Bukau, B. and Horwich, A. L. (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92, 351–366.CrossRefPubMedGoogle Scholar
  13. Calle, E. E. and Kaaks, R. (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4, 579–591.CrossRefPubMedGoogle Scholar
  14. Choo, V. (2002) WHO reassesses appropriate body-mass index for Asian populations. Lancet 360, 235.CrossRefPubMedGoogle Scholar
  15. Elia, M. (2001) Obesity in the elderly. Obes Res 9 Suppl 4, 244S–248S.CrossRefPubMedGoogle Scholar
  16. Expert-Panel (1998) Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 158, 1855–1867.Google Scholar
  17. Fair, A. M. and Montgomery, K. (2009) Energy balance, physical activity, and cancer risk. Methods Mol Biol 472, 57–88.CrossRefPubMedGoogle Scholar
  18. Field, A. E., Coakley, E. H., Must, A., Spadano, J. L., Laird, N., Dietz, W. H., Rimm, E. and Colditz, G. A. (2001) Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch Intern Med 161, 1581–1586.CrossRefPubMedGoogle Scholar
  19. Flegal, K. M., Carroll, M. D., Ogden, C. L. and Johnson, C. L. (2002) Prevalence and trends in obesity among US adults, 1999–2000. J Am Med Assoc 288, 1723–1727.CrossRefGoogle Scholar
  20. Flototto, T., Djahansouzi, S., Glaser, M., Hanstein, B., Niederacher, D., Brumm, C. and Beckmann, M. W. (2001) Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer. Horm Metab Res 33, 451–457.CrossRefPubMedGoogle Scholar
  21. Gastpar, R., Gehrmann, M., Bausero, M. A., Asea, A., Gross, C., Schroeder, J. A. and Multhoff, G. (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65, 5238–5247.CrossRefPubMedGoogle Scholar
  22. Ghayour-Mobarhan, M., Taylor, A., Lamb, D. J. and Ferns, G. A. (2007a) Association between indices of body mass and antibody titres to heat-shock protein-60, -65 and -70 in healthy Caucasians. Int J Obes (Lond) 31, 197–200.CrossRefGoogle Scholar
  23. Ghayour-Mobarhan, M., Yaghootkar, H., Lanham-New, S. A., Lamb, D. J. and Ferns, G. A. (2007b) Association between serum CRP concentrations with dietary intake in healthy and dyslipidaemic patients. Asia Pac J Clin Nutr 16, 262–268.PubMedGoogle Scholar
  24. Gross, M., Ramirez, C., Luthringer, D., Nepomuceno, E., Vollmer, R., Burchette, J. and Freedland, S. J. (2009) Expression of androgen and estrogen related proteins in normal weight and obese prostate cancer patients. Prostate 69, 520–527.Google Scholar
  25. Guzik, T. J., Korbut, R. and Adamek-Guzik, T. (2003) Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 54, 469–487.PubMedGoogle Scholar
  26. Guzik, T. J., Mangalat, D. and Korbut, R. (2006) Adipocytokines – novel link between inflammation and vascular function? J Physiol Pharmacol 57, 505–528.PubMedGoogle Scholar
  27. Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C. Z., Uysal, K. T., Maeda, K., Karin, M. and Hotamisligil, G. S. (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333–336.CrossRefPubMedGoogle Scholar
  28. Hooper, P. L. (1999) Hot-tub therapy for type 2 diabetes mellitus. N Engl J Med 341, 924–925.CrossRefPubMedGoogle Scholar
  29. Hotamisligil, G. S. (2006) Inflammation and metabolic disorders. Nature 444, 860–867.CrossRefPubMedGoogle Scholar
  30. Hotamisligil, G. S., Shargill, N. S. and Spiegelman, B. M. (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91.CrossRefPubMedGoogle Scholar
  31. Housby, J. N., Cahill, C. M., Chu, B., Prevelige, R., Bickford, K., Stevenson, M. A. and Calderwood, S. K. (1999) Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 11, 347–358.CrossRefPubMedGoogle Scholar
  32. Hut, H. M., Kampinga, H. H. and Sibon, O. C. (2005) Hsp70 protects mitotic cells against heat-induced centrosome damage and division abnormalities. Mol Biol Cell 16, 3776–3785.CrossRefPubMedGoogle Scholar
  33. Jaattela, M., Wissing, D., Kokholm, K., Kallunki, T. and Egeblad, M. (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. Embo J 17, 6124–6134.CrossRefPubMedGoogle Scholar
  34. Kaminski, T., Smolinska, N., Gajewska, A., Siawrys, G., Okrasa, S., Kochman, K. and Przala, J. (2006) Leptin and long form of leptin receptor genes expression in the hypothalamus and pituitary during the luteal phase and early pregnancy in pigs. J Physiol Pharmacol 57, 95–108.PubMedGoogle Scholar
  35. Kaur, P., Reis, M., Couchman, G., Forjouh, S. and Asea, A. (2009) Identification of biomarkers linked to diabetes and obesity: a pilot study. (in preparation).Google Scholar
  36. Kern, P. A., Saghizadeh, M., Ong, J. M., Bosch, R. J., Deem, R. and Simsolo, R. B. (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95, 2111–2119.CrossRefPubMedGoogle Scholar
  37. Kershaw, E. E. and Flier, J. S. (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89, 2548–2556.CrossRefPubMedGoogle Scholar
  38. Khandwala, H. M., McCutcheon, I. E., Flyvbjerg, A. and Friend, K. E. (2000) The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 21, 215–244.CrossRefPubMedGoogle Scholar
  39. Konturek, P. C., Konturek, J. W., Czesnikiewicz-Guzik, M., Brzozowski, T., Sito, E. and Konturek, S. J. (2005) Neuro-hormonal control of food intake: basic mechanisms and clinical implications. J Physiol Pharmacol 56 Suppl 6, 5–25.Google Scholar
  40. Konturek, S. J., Konturek, J. W., Pawlik, T. and Brzozowski, T. (2004) Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol 55, 137–154.PubMedGoogle Scholar
  41. Kougias, P., Chai, H., Lin, P. H., Yao, Q., Lumsden, A. B. and Chen, C. (2005) Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. J Surg Res 126, 121–129.CrossRefPubMedGoogle Scholar
  42. Kurucz, I., Morva, A., Vaag, A., Eriksson, K. F., Huang, X., Groop, L. and Koranyi, L. (2002) Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance. Diabetes 51, 1102–1109.CrossRefPubMedGoogle Scholar
  43. Lawlor, M. A. and Alessi, D. R. (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114, 2903–2910.PubMedGoogle Scholar
  44. Le Roith, D. (2000) Regulation of proliferation and apoptosis by the insulin-like growth factor I receptor. Growth Horm IGF Res 10 Suppl A, S.Google Scholar
  45. Lehner, T., Bergmeier, L. A., Wang, Y., Tao, L., Sing, M., Spallek, R. and van der Zee, R. (2000) Heat shock proteins generate beta-chemokines which function as innate adjuvants enhancing adaptive immunity. Eur J Immunol 30, 594–603.CrossRefPubMedGoogle Scholar
  46. Lindquist, S. (1986) The heat-shock response. Annu Rev Biochem 55, 1151–1191.CrossRefPubMedGoogle Scholar
  47. Mayer, M. P. and Bukau, B. (1998) Hsp70 chaperone systems: diversity of cellular functions and mechanism of action. Biol Chem 379, 261–268.PubMedGoogle Scholar
  48. Moschos, S. J. and Mantzoros, C. S. (2002) The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology 63, 317–332.CrossRefPubMedGoogle Scholar
  49. Must, A., Spadano, J., Coakley, E. H., Field, A. E., Colditz, G. and Dietz, W. H. (1999) The disease burden associated with overweight and obesity. J Am Med Assoc 282, 1523–1529.CrossRefGoogle Scholar
  50. Nisoli, E. and Carruba, M. O. (2002) New pharmacological tools for obesity. J Endocrinol Invest 25, 905–914.PubMedGoogle Scholar
  51. Ogden, C. L., Carroll, M. D., Curtin, L. R., McDowell, M. A., Tabak, C. J. and Flegal, K. M. (2006) Prevalence of overweight and obesity in the United States, 1999–2004. J Am Med Assoc 295, 1549–1555.CrossRefGoogle Scholar
  52. Ogden, C. L., Flegal, K. M., Carroll, M. D. and Johnson, C. L. (2002) Prevalence and trends in overweight among US children and adolescents, 1999–2000. J Am Med Assoc 288, 1728–1732.CrossRefGoogle Scholar
  53. Ouchi, N., Kihara, S., Funahashi, T., Matsuzawa, Y. and Walsh, K. (2003) Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 14, 561–566.CrossRefPubMedGoogle Scholar
  54. Panjwani, N. N., Popova, L. and Srivastava, P. K. (2002) Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs. J Immunol 168, 2997–3003.PubMedGoogle Scholar
  55. Park, M. J., Jung, S. R., Jung, H. L., Craig, B. W., Lee, C. D. and Kang, H. Y. (2008) Effects of 4 weeks recombinant human growth hormone administration on insulin resistance of skeletal muscle in rats. Yonsei Med J 49, 1008–1016.CrossRefPubMedGoogle Scholar
  56. Pischon, N., Heng, N., Bernimoulin, J. P., Kleber, B. M., Willich, S. N. and Pischon, T. (2007) Obesity, inflammation, and periodontal disease. J Dent Res 86, 400–409.CrossRefPubMedGoogle Scholar
  57. Prisco, M., Romano, G., Peruzzi, F., Valentinis, B. and Baserga, R. (1999) Insulin and IGF-I receptors signaling in protection from apoptosis. Horm Metab Res 31, 80–89.CrossRefPubMedGoogle Scholar
  58. Rivlin, R. S. (2007) Keeping the young-elderly healthy: is it too late to improve our health through nutrition? Am J Clin Nutr 86, 1572S–1576S.PubMedGoogle Scholar
  59. Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R. and Kern, P. A. (1996) The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97, 1111–1116.CrossRefPubMedGoogle Scholar
  60. Saijo, Y., Kiyota, N., Kawasaki, Y., Miyazaki, Y., Kashimura, J., Fukuda, M. and Kishi, R. (2004) Relationship between C-reactive protein and visceral adipose tissue in healthy Japanese subjects. Diabetes Obes Metab 6, 249–258.CrossRefPubMedGoogle Scholar
  61. Sheng, T. and Yang, K. (2008) Adiponectin and its association with insulin resistance and type 2 diabetes. J Genet Genomics 35, 321–326.CrossRefPubMedGoogle Scholar
  62. Sims, T. J., Lernmark, A., Mancl, L. A., Schifferle, R. E., Page, R. C. and Persson, G. R. (2002) Serum IgG to heat shock proteins and Porphyromonas gingivalis antigens in diabetic patients with periodontitis. J Clin Periodontol 29, 551–562.CrossRefPubMedGoogle Scholar
  63. Srivastava, P. K. (2000) Heat shock protein-based novel immunotherapies. Drug News Perspect 13, 517–522.CrossRefPubMedGoogle Scholar
  64. Srivastava, P. K. (2005) Immunotherapy for human cancer using heat shock protein-peptide complexes. Curr Oncol Rep 7, 104–108.CrossRefPubMedGoogle Scholar
  65. Srivastava, P. K., Udono, H., Blachere, N. E. and Li, Z. (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39, 93–98.CrossRefPubMedGoogle Scholar
  66. Stallmeyer, B., Pfeilschifter, J. and Frank, S. (2001) Systemically and topically supplemented leptin fails to reconstitute a normal angiogenic response during skin repair in diabetic ob/ob mice. Diabetologia 44, 471–479.CrossRefPubMedGoogle Scholar
  67. Stumvoll, M., Goldstein, B. J. and van Haeften, T. W. (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346.CrossRefPubMedGoogle Scholar
  68. Tang, D., Xie, Y., Zhao, M., Stevenson, M. A. and Calderwood, S. K. (2001) Repression of the HSP70B promoter by NFIL6, Ku70, and MAPK involves three complementary mechanisms. Biochem Biophys Res Commun 280, 280–285.CrossRefPubMedGoogle Scholar
  69. Thompson, D. and Wolf, A. M. (2001) The medical-care cost burden of obesity. Obes Rev 2, 189–197.CrossRefPubMedGoogle Scholar
  70. Tilg, H. and Moschen, A. R. (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6, 772–783.CrossRefPubMedGoogle Scholar
  71. Trayhurn, P. and Wood, I. S. (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33, 1078–1081.CrossRefPubMedGoogle Scholar
  72. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. and Hotamisligil, G. S. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614.CrossRefPubMedGoogle Scholar
  73. Yee, D. (2001) Are the insulin-like growth factors relevant to cancer? Growth Horm IGF Res 11, 339–345.CrossRefPubMedGoogle Scholar
  74. Zimmet, P., Magliano, D., Matsuzawa, Y., Alberti, G. and Shaw, J. (2005) The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb 12, 295–300.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Punit Kaur
    • 1
  • Michael D. Reis
    • 2
  • Glen R. Couchman
    • 2
  • Samuel N. Forjuoh
    • 2
  • John F. GreeneJr
    • 1
  • Alexzander Asea
    • 1
    • 3
    Email author
  1. 1.Division of Investigative PathologyThe Texas A&M Health Science Center College of Medicine, Scott & White Memorial Hospital and ClinicTempleUSA
  2. 2.Department of Family & Community MedicineThe Texas A&M Health Science Center College of Medicine, Scott & White Memorial Hospital and ClinicTempleUSA
  3. 3.Division of Investigative PathologyThe Texas A&M Health Science Center College of Medicine, Scott & White Memorial Hospital and ClinicTempleUSA

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