Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet.

Animals; Diet, High-Fat; Endoplasmic Reticulum Stress/genetics; Energy Metabolism/genetics; Fatty Acids/blood; Glucose Intolerance; Glucose Tolerance Test; Male; Mice; Mice, Knockout; Obesity/genetics/metabolism; Signal Transduction; Toll-Like Receptor 4/deficiency/genetics/metabolism

Abstract :

[en] The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4(-/-) and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2alpha. TLR4(-/-) mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-kappaB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-kappaB namely TNFalpha, IL-1beta and IL-6, were not changed after HFD and phospho-IkappaB-alpha (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFkappa-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4(-/-) mice could explain the absence of an ER stress after HFD.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Pierre, Nicolas ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie

Deldicque, Louise

Barbe, Caroline

Naslain, Damien

Cani, Patrice D.

Francaux, Marc

Language :

English

Title :

Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet.

Publication date :

2013

Journal title :

PLoS ONE

eISSN :

1932-6203

Publisher :

Public Library of Science, United States - California

Volume :

Issue :

Pages :

e65061

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 18 June 2019

Statistics

Number of views

66 (5 by ULiège)

Number of downloads

42 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Greenberg AS, Obin MS, (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83: 461S-465S.
Wellen KE, Hotamisligil GS, (2005) Inflammation, stress, and diabetes. J Clin Invest 115: 1111-1119.
Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, et al. (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114: 823-827.
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, et al. (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293: 1673-1677.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420: 333-336.
Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, et al. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271: 665-668.
Schaffer JE, (2003) Lipotoxicity: when tissues overeat. Curr Opin Lipidol 14: 281-287.
Roden M, Krssak M, Stingl H, Gruber S, Hofer A, et al. (1999) Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48: 358-364.
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, et al. (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97: 2859-2865.
Summers SA, (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45: 42-72.
Idris I, Gray S, Donnelly R, (2001) Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia 44: 659-673.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116: 3015-3025.
Lee JY, Sohn KH, Rhee SH, Hwang D, (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276: 16683-16689.
Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117: 979-987; quiz 988.
Miyake K, (2004) Endotoxin recognition molecules, Toll-like receptor 4-MD-2. Semin Immunol 16: 11-16.
Radin MS, Sinha S, Bhatt BA, Dedousis N, O'Doherty RM, (2008) Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle. Diabetologia 51: 336-346.
Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, et al. (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56: 1986-1998.
Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, et al. (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100: 1589-1596.
Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME, (2008) Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring) 16: 1248-1255.
Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, et al. (2007) C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50: 1267-1276.
Boden G, (2009) Endoplasmic reticulum stress: another link between obesity and insulin resistance/inflammation? Diabetes 58: 518-519.
Tsiotra PC, Tsigos C, (2006) Stress, the endoplasmic reticulum, and insulin resistance. Ann N Y Acad Sci 1083: 63-76.
Zhang K, Kaufman RJ, (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454: 455-462.
Deldicque L, Cani PD, Philp A, Raymackers JM, Meakin PJ, et al. (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: E695-705.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306: 457-461.
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, et al. (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664-666.
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, et al. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162: 3749-3752.
Cani PD, Dewever C, Delzenne NM, (2004) Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br J Nutr 92: 521-526.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, et al. (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034.
Akira S, Sato S, (2003) Toll-like receptors and their signaling mechanisms. Scand J Infect Dis 35: 555-562.
Lee AS, (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26: 504-510.
Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, et al. (1996) Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol Cell Biol 16: 4273-4280.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K, (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881-891.
Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, et al. (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16: 452-466.
Nolan T, Hands RE, Bustin SA, (2006) Quantification of mRNA using real-time RT-PCR. Nat Protoc 1: 1559-1582.
Ye R, Jung DY, Jun JY, Li J, Luo S, et al. (2010) Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes 59: 6-16.
Malhotra JD, Kaufman RJ, (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18: 716-731.
Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D, (2008) Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 7: 520-532.
Novoa I, Zeng H, Harding HP, Ron D, (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153: 1011-1022.
Williams BR, (1999) PKR; a sentinel kinase for cellular stress. Oncogene 18: 6112-6120.
Berlanga JJ, Santoyo J, De Haro C, (1999) Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Eur J Biochem 265: 754-762.
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, et al. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761-1772.
Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, et al. (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57: 1470-1481.
Kim KA, Gu W, Lee IA, Joh EH, Kim DH, (2012) High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway. PLoS One 7: e47713.
Endo M, Mori M, Akira S, Gotoh T, (2006) C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J Immunol 176: 6245-6253.
Kuribayashi JS, Bombardieri CR, Baracho GV, Aliberti J, Machado FS, et al. (2008) Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency. Mol Immunol 45: 2990-2997.
Kozlov AV, Duvigneau JC, Miller I, Nurnberger S, Gesslbauer B, et al. (2009) Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. Biochim Biophys Acta 1792: 521-530.
Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, et al. (2011) Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 300: G956-967.
Gao S, He L, Ding Y, Liu G, (2010) Mechanisms underlying different responses of plasma triglyceride to high-fat diets in hamsters and mice: roles of hepatic MTP and triglyceride secretion. Biochem Biophys Res Commun 398: 619-626.
Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, et al. (2009) Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10: 419-429.
Frisard MI, McMillan RP, Marchand J, Wahlberg KA, Wu Y, et al. (2010) Toll-like receptor 4 modulates skeletal muscle substrate metabolism. Am J Physiol Endocrinol Metab 298: E988-998.
Srinivasan V, Tatu U, Mohan V, Balasubramanyam M, (2009) Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells. Mol Cell Biochem 328: 217-224.
Buse MG, (2006) Hexosamines, insulin resistance, and the complications of diabetes: current status. Am J Physiol Endocrinol Metab 290: E1-E8.
Younce CW, Wang K, Kolattukudy PE, (2010) Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP. Cardiovasc Res 87: 665-674.
Sheikh-Ali M, Sultan S, Alamir AR, Haas MJ, Mooradian AD, (2010) Hyperglycemia-induced endoplasmic reticulum stress in endothelial cells. Nutrition 26: 1146-1150.
Beriault DR, Sharma S, Shi Y, Khan MI, Werstuck GH (2011) Glucosamine-supplementation promotes endoplasmic reticulum stress, hepatic steatosis and accelerated atherogenesis in apoE-/- mice. Atherosclerosis.
Alhusaini S, McGee K, Schisano B, Harte A, McTernan P, et al. (2010) Lipopolysaccharide, high glucose and saturated fatty acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. Biochem Biophys Res Commun 397: 472-478.
Dutta K, Podolin DA, Davidson MB, Davidoff AJ, (2001) Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance. Diabetes 50: 1186-1192.
Pagliassotti MJ, Shahrokhi KA, Moscarello M, (1994) Involvement of liver and skeletal muscle in sucrose-induced insulin resistance: dose-response studies. Am J Physiol 266: R1637-1644.
Omar B, Pacini G, Ahren B, (2012) Differential development of glucose intolerance and pancreatic islet adaptation in multiple diet induced obesity models. Nutrients 4: 1367-1381.
Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, et al. (2008) Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 57: 2595-2602.
Lambert CP, Wright NR, Finck BN, Villareal DT, (2008) Exercise but not diet-induced weight loss decreases skeletal muscle inflammatory gene expression in frail obese elderly persons. J Appl Physiol 105: 473-478.
Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, et al. (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134: 568-576.
Boden G, Duan X, Homko C, Molina EJ, Song W, et al. (2008) Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 57: 2438-2444.
Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, et al. (2009) Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58: 693-700.
Kim JJ, Sears DD (2010) TLR4 and Insulin Resistance. Gastroenterol Res Pract 2010.
Zhang X, Zhang K, (2012) Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes. Biochem Res Int 2012: 247275.