Abstract
Certain conditions, such as several weeks of high-fat diet, disrupt endoplasmic reticulum (ER) homeostasis and activate an adaptive pathway referred as the unfolded protein response. When the unfolded protein response fails, the result is the development of inflammation and insulin resistance. These two pathological states are known to be improved by regular exercise training but the mechanisms remain largely undetermined. As it has recently been shown that the unfolded protein response is regulated by exercise, we hypothesised that concomitant treadmill exercise training (HFD+ex) prevents ER homeostasis disruption and its downstream consequences induced by a 6-week high-fat diet (HFD) in mice by activating the protective unfolded protein response. Several well-documented markers of the unfolded protein response were measured in the soleus and tibialis anterior muscles as well as in the liver and pancreas. In HFD mice, an increase in these markers was observed (from 2- to 15-fold, P < 0.05) in all tissues studied. The combination of HFD+ex increased the expression of several markers further, up to 100 % compared to HFD alone (P < 0.05). HFD increased inflammatory markers both in the plasma (IL-6 protein, 2.5 ± 0.52-fold; MIP-1α protein, 1.3 ± 0.13-fold; P < 0.05) and in the tissues studied, and treadmill exercise attenuated the inflammatory state induced by HFD (P < 0.05). However, treadmill exercise could not reverse HFD-induced whole body glucose intolerance, assessed by OGTT (AUC, 1.8 ± 0.29-fold, P < 0.05). In conclusion, our results show that a HFD activated the unfolded protein response in mouse tissues in vivo, and that endurance training promoted this response. We speculate that the potentiation of the unfolded protein response by endurance training may represent a positive adaptation protecting against further cellular stress.
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References
Bradley RL, Jeon JY, Liu FF, Maratos-Flier E (2008) Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice. Am J Physiol Endocrinol Metab 295:586–594
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772
Cani PD, Knauf C, Iglesias MA, Drucker DJ, Delzenne NM, Burcelin R (2006) Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor. Diabetes 55:1484–1490
Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091–1103
da Luz G, Frederico MJ, da SS, Vitto MF, Cesconetto PA, de Pinho RA, Pauli JR, Silva AS, Cintra DE, Ropelle ER, De Souza CT (2011) Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. Eur J Appl Physiol
Deldicque L, Cani PD, Philp A, Raymackers JM, Meakin PJ, Ashford ML, Delzenne NM, Francaux M, Baar K (2010) The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis. Am J Physiol Endocrinol Metab 299:E695–E705
Deldicque L, Van Proeyen K, Francaux M, Hespel P (2010) The unfolded protein response in human skeletal muscle is not involved in the onset of glucose tolerance impairment induced by a fat-rich diet. Eur J Appl Physiol
Desilva MG, Notkins AL, Lan MS (1997) Molecular characterization of a pancreas-specific protein disulfide isomerase, PDIp. DNA Cell Biol 16:269–274
Dzamko N, Schertzer JD, Ryall JG, Steel R, Macaulay SL, Wee S, Chen ZP, Michell BJ, Oakhill JS, Watt MJ, Jorgensen SB, Lynch GS, Kemp BE, Steinberg GR (2008) AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. J Physiol 586:5819–5831
Gauthier MS, Couturier K, Latour JG, Lavoie JM (2003) Concurrent exercise prevents high-fat-diet-induced macrovesicular hepatic steatosis. J Appl Physiol 94:2127–2134
Gregor MF, Hotamisligil GS (2007) Thematic review series: adipocyte biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905–1914
Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26:3071–3084
Ikesugi K, Mulhern ML, Madson CJ, Hosoya K, Terasaki T, Kador PF, Shinohara T (2006) Induction of endoplasmic reticulum stress in retinal pericytes by glucose deprivation. Curr Eye Res 31:947–953
Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y (2005) Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J Mol Med 83:429–439
Kim CH, Youn JH, Park JY, Hong SK, Park KS, Park SW, Suh KI, Lee KU (2000) Effects of high-fat diet and exercise training on intracellular glucose metabolism in rats. Am J Physiol Endocrinol Metab 278:977–984
Kim DS, Jeong SK, Kim HR, Chae SW, Chae HJ (2007) Effects of triglyceride on ER stress and insulin resistance. Biochem Biophys Res Commun 363:140–145
Kim HJ, Jamart C, Deldicque L, An GL, Lee YH, Kim CK, Raymackers JM, Francaux M (2011) Endoplasmic reticulum stress markers and ubiquitin-proteasome pathway activity in response to a 200-km run. Med Sci Sports Exerc 43:18–25
Kitamura M (2011) Control of NF-kappaB and inflammation by the unfolded protein response. Int Rev Immunol 30:4–15
Kraegen EW, Storlien LH, Jenkins AB, James DE (1989) Chronic exercise compensates for insulin resistance induced by a high-fat diet in rats. Am J Physiol 256:242–249
Lang CH, Silvis C, Deshpande N, Nystrom G, Frost RA (2003) Endotoxin stimulates in vivo expression of inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, -6, and high-mobility-group protein-1 in skeletal muscle. Shock 19:538–546
Lipson KL, Fonseca SG, Urano F (2006) Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr Mol Med 6:71–77
Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731
Miller WC, Bryce GR, Conlee RK (1984) Adaptations to a high-fat diet that increase exercise endurance in male rats. J Appl Physiol 56:78–83
Mills KH, Dunne A (2009) Immune modulation: IL-1, master mediator or initiator of inflammation. Nat Med 15:1363–1364
Miura S, Kai Y, Kamei Y, Bruce CR, Kubota N, Febbraio MA, Kadowaki T, Ezaki O (2009) Alpha2-AMPK activity is not essential for an increase in fatty acid oxidation during low-intensity exercise. Am J Physiol Endocrinol Metab 296:E47–E55
Romijn JA, Coyle EF, Sidossis LS, Zhang XJ, Wolfe RR (1995) Relationship between fatty acid delivery and fatty acid oxidation during strenuous exercise. J Appl Physiol 79:1939–1945
Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529
Schefer V, Talan MI (1996) Oxygen consumption in adult and AGED C57BL/6J mice during acute treadmill exercise of different intensity. Exp Gerontol 31:387–392
Straczkowski M, Kowalska I, Dzienis-Straczkowska S, Kinalski M, Gorski J, Kinalska I (2001) The effect of exercise training on glucose tolerance and skeletal muscle triacylglycerol content in rats fed with a high-fat diet. Diabetes Metab 27:19–23
Szegezdi E, Fitzgerald U, Samali A (2003) Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann N Y Acad Sci 1010:186–194
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666
Vieira VJ, Valentine RJ, Wilund KR, Antao N, Baynard T, Woods JA (2009) Effects of exercise and low-fat diet on adipose tissue inflammation and metabolic complications in obese mice. Am J Physiol Endocrinol Metab 296:E1164–E1171
Wu J, Kaufman RJ (2006) From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ 13:374–384
Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Bostrom P, Tyra HM, Crawford RW, Campbell KP, Rutkowski DT, Kaufman RJ, Spiegelman BM (2011) The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1alpha/ATF6alpha complex. Cell Metab 13:160–169
Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276:13935–13940
Zhang K, Kaufman RJ (2006) Protein folding in the endoplasmic reticulum and the unfolded protein response. Handb Exp Pharmacol 69-91
Acknowledgements
The authors would like to thank Damien Naslain, Delphine Robin, Gang-Li An and Vincent d’Harveng for their technical assistance.
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This work was supported by the Fonds National de la Recherche Scientifique (Belgium), by the Université catholique de Louvain (FSR) and by the Chaire Delhaize (Belgium). At the time of data collection, L. Deldicque was a postdoctoral fellow from the FRS-FNRS (Fonds de la Recherche Scientifique), Belgium. P. Cani is Research Associate from the FRS-FNRS, Belgium.
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Deldicque, L., Cani, P.D., Delzenne, N.M. et al. Endurance training in mice increases the unfolded protein response induced by a high-fat diet. J Physiol Biochem 69, 215–225 (2013). https://doi.org/10.1007/s13105-012-0204-9
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DOI: https://doi.org/10.1007/s13105-012-0204-9