Immunohistochemical profiling of the heat shock response in obese non-diabetic subjects revealed impaired expression of heat shock proteins in the adipose tissue
Tóm tắt
Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels. Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects. Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P < 0.05). No differential expression was observed for HSP-27 between the two groups. Higher levels of HSP-72 and GRP-94 proteins correlated positively with the indices of obesity (body mass index and percent body fat) and circulating levels of IFN-gamma-inducible protein 10 (IP-10) and RANTES chemokines. This expression pattern was concomitant with increased inflammatory response in the adipose tissue as monitored by increased levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and RANTES (P < 0.05). Physical exercise reduced the expression of various HSPs in obese to normal levels observed in lean subjects with a parallel decrease in the endogenous levels of IL-6, TNF-α, and RANTES. Taken together, these data indicate that obesity triggers differential regulation of various components of the HSR in non-diabetic subjects and a 3-month physical moderate exercise was sufficient to restore the normal expression of HSPs in the adipose tissue with concomitant attenuation in the inflammatory response.
Tài liệu tham khảo
Olshansky SJ, Passaro DJ, Hershow RC, Layden J, Carnes BA, Brody J, Hayflick L, Butler RN, Allison DB, Ludwig DS: A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005, 352: 1138-1145.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003, 289: 76-79.
Teixeira-Lemos E, Nunes S, Teixeira F, Reis F: Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovasc Diabetol. 2011, 10: 12-
Hotamisligil GS: Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010, 140: 900-917.
Bruce CR, Carey AL, Hawley JA, Febbraio MA: 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. 2003, 52: 2338-2345.
Kurucz I, Morva A, Vaag A, Eriksson KF, Huang X, Groop L, Koranyi L: Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance. Diabetes. 2002, 51: 1102-1109.
Helmut S: Oxidative Stress and Inflammatory Mechanisms in Obesity, Diabetes, and the Metabolic Syndrome. Oxidative Stress and Disease. 2007, London: CRC Press, 1,
Liu J, Shen W, Zhao B, Wang Y, Wertz K, Weber P, Zhang P: Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients. Adv Drug Deliv Rev. 2009, 61: 1343-1352.
Chiang WC, Ching TT, Lee HC, Mousigian C, Hsu AL: HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell. 2012, 148: 322-334.
McCarty MF: Induction of heat shock proteins may combat insulin resistance. Med Hypotheses. 2006, 66: 527-534.
Voellmy R, Voellmy R: Feedback regulation of the heat shock response. Handb Exp Pharmacol. 2006, 172: 43-68.
Voellmy R, Boellmann F: Chaperone regulation of the heat shock protein response. Adv Exp Med Biol. 2007, 594: 89-99.
Westerheide SD, Morimoto RI: Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem. 2005, 280: 33097-33100.
Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK: Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem. 2002, 277: 15028-15034.
Johnson JD, Fleshner M: Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J Leukoc Biol. 2006, 79: 425-434.
Noble EG, Milne KJ, Melling CW: Heat shock proteins and exercise: a primer. Appl Physiol Nutr Metab. 2008, 33: 1050-1065.
Najemnikova E, Rodgers CD, Locke M: Altered heat stress response following streptozotocin-induced diabetes. Cell Stress Chaperones. 2007, 12: 342-352.
Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA: HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A. 2008, 105: 1739-1744.
Sarkozy M, Zvara A, Gyemant N, Fekete V, Kocsis GF, Pipis J, Szucs G, Csonka C, Puskas LG, Ferdinandy P, Csont T: Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats. Cardiovasc Diabetol. 2013, 12: 16-
Martin JL, Mestril R, Hilal-Dandan R, Brunton LL, Dillmann WH: Small heat shock proteins and protection against ischemic injury in cardiac myocytes. Circulation. 1997, 96: 4343-4348.
Stice JP, Chen L, Kim SC, Jung JS, Tran AL, Liu TT, Knowlton AA: 17beta-Estradiol, aging, inflammation, and the stress response in the female heart. Endocrinology. 2011, 152: 1589-1598.
Starnes JW, Choilawala AM, Taylor RP, Nelson MJ, Delp MD: Myocardial heat shock protein 70 expression in young and old rats after identical exercise programs. J Gerontol A Biol Sci Med Sci. 2005, 60: 963-969.
Novo G, Cappello F, Rizzo M, Fazio G, Zambuto S, Tortorici E, Marino Gammazza A, Corrao S, Zummo G, De Macario EC, Macario AJ, Assennato P, Novo S, Li Volti G: Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction. Transl Res. 2011, 157: 285-292.
Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, Pockley AG, Hu FB, Wu T: Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation. 2008, 118: 2687-2693.
Gupte AA, Bomhoff GL, Swerdlow RH, Geiger PC: Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes. 2009, 58: 567-578.
Morino S, Kondo T, Sasaki K, Adachi H, Suico MA, Sekimoto E, Matsuda T, Shuto T, Araki E, Kai H: Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. PLoS One. 2008, 3: e4068-
Gupte AA, Bomhoff GL, Morris JK, Gorres BK, Geiger PC: Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscle from high-fat-fed rats. J Appl Physiol. 2009, 106: 1425-1434.
Literati-Nagy B, Kulcsar E, Literati-Nagy Z, Buday B, Peterfai E, Horvath T, Tory K, Kolonics A, Fleming A, Mandl J, Koranyi L: Improvement of insulin sensitivity by a novel drug, BGP-15, in insulin-resistant patients: a proof of concept randomized double-blind clinical trial. Horm Metab Res. 2009, 41: 374-380.
Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, Dermime S: Expression of B7-H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer. 2007, 121: 751-758.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001, 25: 402-408.
Abubaker J, Tiss A, Abu-Farha M, Al-Ghimlas F, Al-Khairi I, Baturcam E, Cherian P, Elkum N, Hammad M, John J, Kavalakatt S, Khadir A, Warsame S, Dermime S, Behbehani K, Dehbi M: DNAJB3/HSP-40 Cochaperone Is Downregulated in Obese Humans and Is Restored by Physical Exercise. PLoS One. 2013, 8: e69217-
Baturcam E, Abubaker J, Tiss A, Abu-Farha M, Khadir A, Al-Ghimlas F, Al-Khairi I, Cherian P, Elkum N, Hammad M, John J, Kavalakatt S, Lehe C, Warsame S, Behbehani K, Dermime S, Dehbi M: Physical exercise reduces the expression of RANTES and its CCR5 receptor in the adipose tissue of obese humans. Mediators Inflamm. 2014, 2014: 627150-
Gregor MF, Hotamisligil GS: Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011, 29: 415-445.
Kondo T, Koga S, Matsuyama R, Miyagawa K, Goto R, Kai H, Araki E: Heat shock response regulates insulin sensitivity and glucose homeostasis: pathophysiological impact and therapeutic potential. Curr Diabetes Rev. 2011, 7: 264-269.
Hooper PL, Hooper PL: Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress Chaperones. 2009, 14: 113-115.
Kalmar B, Greensmith L: Induction of heat shock proteins for protection against oxidative stress. Adv Drug Deliv Rev. 2009, 61: 310-318.
McArdle A, Jackson M: Stress proteins and exercise-induced muscle damage. Exercise and Stress Response. The Role of Stress Proteins. Edited by: Locke FM, Noble EG, Boca R. 2002, 137-150. London: CRC,
Morton JP, MacLaren DP, Cable NT, Bongers T, Griffiths RD, Campbell IT, Evans L, Kayani A, McArdle A, Drust B: Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise. J Appl Physiol (1985). 2006, 101: 176-182.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature. 2002, 420: 333-336.
Whitham M, Laing SJ, Jackson A, Maassen N, Walsh NP: Effect of exercise with and without a thermal clamp on the plasma heat shock protein 72 response. J Appl Physiol (1985). 2007, 103: 1251-1256.
Gupte AA, Bomhoff GL, Touchberry CD, Geiger PC: Acute heat treatment improves insulin-stimulated glucose uptake in aged skeletal muscle. J Appl Physiol. 2011, 110: 451-457.
Hagiwara S, Iwasaka H, Shingu C, Matsumoto S, Hasegawa A, Asai N, Noguchi T: Heat shock protein 72 protects insulin-secreting beta cells from lipopolysaccharide-induced endoplasmic reticulum stress. Int J Hyperthermia. 2009, 25: 626-633.
Marker T, Sell H, Zillessen P, Glode A, Kriebel J, Ouwens DM, Pattyn P, Ruige J, Famulla S, Roden M, Eckel J, Habich C: Heat shock protein 60 as a mediator of adipose tissue inflammation and insulin resistance. Diabetes. 2012, 61: 615-625.
Henstridge DC, Forbes JM, Penfold SA, Formosa MF, Dougherty S, Gasser A, de Courten MP, Cooper ME, Kingwell BA, de Courten B: The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity. Metabolism. 2010, 59: 1556-1561.
Kavanagh K, Zhang L, Wagner JD: Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys. Cell Stress Chaperones. 2009, 14: 291-299.
Gillum T, Kuennen M, Gourley C, Dokladny K, Schneider S, Moseley P: Sex differences in heat shock protein 72 expression in peripheral blood mononuclear cells to acute exercise in the heat. Int J Endocrinol Metab. 2013, 11: e8739-
Njemini R, Bautmans I, Onyema OO, Van Puyvelde K, Demanet C, Mets T: Circulating heat shock protein 70 in health, aging and disease. BMC Immunol. 2011, 12: 24-
Rodrigues-Krause J, Krause M, O’Hagan C, De Vito G, Boreham C, Murphy C, Newsholme P, Colleran G: Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter?. Cell Stress Chaperones. 2012, 17: 293-302.
Ogawa K, Seta R, Shimizu T, Shinkai S, Calderwood SK, Nakazato K, Takahashi K: Plasma adenosine triphosphate and heat shock protein 72 concentrations after aerobic and eccentric exercise. Exerc Immunol Rev. 2011, 17: 136-149.
Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA: Exercise increases serum Hsp72 in humans. Cell Stress Chaperones. 2001, 6: 386-393.
Peake J, Nosaka K, Suzuki K: Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev. 2005, 11: 64-85.
Hirose L, Nosaka K, Newton M, Laveder A, Kano M, Peake J, Suzuki K: Changes in inflammatory mediators following eccentric exercise of the elbow flexors. Exerc Immunol Rev. 2004, 10: 75-90.
Noble EG, Shen GX: Impact of exercise and metabolic disorders on heat shock proteins and vascular inflammation. Autoimmune Dis. 2012, 2012: 836519-
Harris MB, Starnes JW: Effects of body temperature during exercise training on myocardial adaptations. Am J Physiol Heart Circ Physiol. 2001, 280: H2271-H2280.
Milne KJ, Thorp DB, Krause M, Noble EG: Core temperature is a greater influence than endogenous 17beta-estradiol on the exercise-induced accumulation of myocardial heat shock protein mRNA. Can J Physiol Pharmacol. 2011, 89: 855-860,
Paulsen G, Vissing K, Kalhovde JM, Ugelstad I, Bayer ML, Kadi F, Schjerling P, Hallen J, Raastad T: Maximal eccentric exercise induces a rapid accumulation of small heat shock proteins on myofibrils and a delayed HSP70 response in humans. Am J Physiol Regul Integr Comp Physiol. 2007, 293: R844-R853.