ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

Abstract

The endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signaling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E β-cells dependent on the degree of ER stress. It appears that ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis.

ER stress - insulin signaling - insulin resistance - adipocytes - adipokines

References

• 1 Araki E, Oyadomari S, Mori M. Endoplasmic reticulum stress and diabetes mellitus.  Internal Med. 2003;  42 7-14
• 2 Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.  Science. 2004;  306 457-461
• 3 Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.  Science. 2000;  287 664-666
• 4 Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).  J Biol Chem. 2000;  275 9047-9054
• 5 Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade.  J Biol Chem. 2003;  278 2896-2902
• 6 White MF. IRS proteins and the common path to diabetes.  Am J Physiol Endocrinol Metabol. 2002;  283 E413-E422
• 7 Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.  J Biol Chem. 2003;  278 14599-14602
• 8 Larance M, Ramm G, Stockli J, van Dam EM, Winata S, Wasinger V, Simpson F, Graham M, Junutula JR, Guilhaus M, James DE. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking.  J Biol Chem. 2005;  280 37803-37813
• 9 Eguez L, Lee A, Chavez JA, Miinea CP, Kane S, Lienhard GE, McGraw TE. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein.  Cell Metab. 2005;  2 263-272
• 10 Sethi JK, Vidal-Puig AJ. Thematic review series: Adipocyte Biology. Adipose tissue function and plasticity orchestrate nutritional adaptation.  J Lipid Res. 2007;  48 1253-1262
• 11 Eckardt K, Sell H, Taube A, Koenen M, Platzbecker B, Cramer A, Horrighs A, Lehtonen M, Tennagels N, Eckel J. Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle.  Diabetologia. 2009;  52 664-674
• 12 Zhou L, Sell H, Eckardt K, Yang Z, Eckel J. Conditioned medium obtained from in vitro differentiated adipocytes and resistin induce insulin resistance in human hepatocytes.  FEBS Lett. 2007;  581 4303-4308
• 13 Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent?.  Diabetes. 2005;  54 (S 02) S114-S124
• 14 Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.  JAMA. 2001;  286 327-334
• 15 Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.  Diabetes. 2003;  52 812-817
• 16 Nieto-Vazquez I, Fernandez-Veledo S, de Alvaro C, Lorenzo M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.  Diabetes. 2008;  57 3211-3221
• 17 Southern C, Schulster D, Green IC. Inhibition of insulin secretion from rat islets of Langerhans by interleukin-6. An effect distinct from that of interleukin-1.  Biochem J. 1990;  272 243-245
• 18 Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity.  Endocrinology. 2005;  146 3417-3427
• 19 Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice.  Diabetes. 2003;  52 2784-2789
• 20 Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR, Cline G, Kim YB, Kim JK. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.  Diabetes. 2004;  53 1060-1067
• 21 Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.  J Clin Invest. 2006;  116 1784-1792
• 22 Yang R, Barouch LA. Leptin signaling and obesity: cardiovascular consequences.  Circ Res. 2007;  101 545-559
• 23 Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.  Science. 2003;  300 1574-1577
• 24 Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori M, Yamasaki Y, Matsuhisa M. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes.  J Biol Chem. 2005;  280 847-851
• 25 Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.  Science. 2006;  313 1137-1140
• 26 Ozawa K, Miyazaki M, Matsuhisa M, Takano K, Nakatani Y, Hatazaki M, Tamatani T, Yamagata K, Miyagawa J, Kitao Y, Hori O, Yamasaki Y, Ogawa S. The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.  Diabetes. 2005;  54 657-663
• 27 Scheuner D, Song BB, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ. Translational control is required for the unfolded protein response and in vivo glucose homeostasis.  Molecular Cell. 2001;  7 1165-1176
• 28 Gregor MF, Hotamisligil GS. Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease.  J Lipid Res. 2007;  48 1905-1914
• 29 Merglen A, Theander S, Rubi B, Chaffard G, Wollheim CB, Maechler P. Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells.  Endocrinology. 2004;  145 667-678
• 30 Mohanty S, Spinas GA, Maedler K, Zuellig RA, Lehmann R, Donath MY, Trub T, Niessen M. Overexpression of IRS2 in isolated pancreatic islets causes proliferation and protects human beta-cells from hyperglycemia-induced apoptosis.  Exp Cell Res. 2005;  303 68-78
• 31 Rudich A, Konrad D, Torok D, Ben-Romano R, Huang C, Niu W, Garg RR, Wijesekara N, Germinario RJ, Bilan PJ, Klip A. Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues.  Diabetologia. 2003;  46 649-658
• 32 Wueest S, Rapold RA, Rytka JM, Schoenle EJ, Konrad D. Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice.  Diabetologia. 2009;  52 541-546
• 33 Wueest S, Rapold RA, Rytka JM, Schoenle EJ, Konrad D. Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice.  Diabetologia. 2009;  52 541-546
• 34 Niessen M, Jaschinski F, Item F, McNamara MP, Spinas GA, Trub T. Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells.  Exp Cell Res. 2007;  313 805-815
• 35 Zaid H, Antonescu CN, Randhawa VK, Klip A. Insulin action on glucose transporters through molecular switches, tracks and tethers.  Biochem J. 2008;  413 201-215
• 36 Hoehn KL, Hohnen-Behrens C, Cederberg A, Wu LE, Turner N, Yuasa T, Ebina Y, James DE. IRS1-independent defects define major nodes of insulin resistance.  Cell Metab. 2008;  7 421-433
• 37 Miller RS, Diaczok D, Cooke DW. Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2007;  362 188-192
• 38 Wertheimer E, Sasson S, Cerasi E, Ben-Neriah Y. The ubiquitous glucose transporter GLUT-1 belongs to the glucose-regulated protein family of stress-inducible proteins.  Proc Natl Acad Sci USA. 1991;  88 2525-2529
• 39 Gliemann J, Gammeltoft S, Vinten J. Time course of insulin-receptor binding and insulin-induced lipogenesis in isolated rat fat cells.  J Biol Chem. 1975;  250 3368-3374
• 40 Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1.  Science. 2008;  320 1492-1496
• 41 Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice.  Cell Metab. 2008;  7 520-532
• 42 Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferré P, Foufelle F. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice.  J Clin Invest. 2009;  119 1201-1215
• 43 Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. 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. 2006;  26 3071-3084
• 44 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.  Diabetes. 2007;  56 901-911
• 45 Ehses JA, Boni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes.  Biochem Soc Trans. 2008;  36 340-342
• 46 Maedler K. Beta cells in type 2 diabetes - a crucial contribution to pathogenesis.  Diabetes Obes Metab. 2008;  10 408-420
• 47 Ellingsgaard H, Ehses JA, Hammar EB, Van Lommel L, Quintens R, Martens G, Kerr-Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit FC, Donath MY. Interleukin-6 regulates pancreatic alpha-cell mass expansion.  Proc Natl Acad Sci USA. 2008;  105 13163-13168

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