Subscribe to RSS
DOI: 10.1055/s-0030-1255034
© Georg Thieme Verlag KG Stuttgart · New York
ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport
Publication History
received 09.02.2010
accepted 10.05.2010
Publication Date:
17 June 2010 (online)

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.
Key words
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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 6
White MF.
IRS proteins and the common path to diabetes.
Am J Physiol Endocrinol Metabol.
2002;
283
E413-E422
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 13
Kristiansen OP, Mandrup-Poulsen T.
Interleukin-6 and diabetes: the good, the bad, or the indifferent?.
Diabetes.
2005;
54
(S 02)
S114-S124
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 18
Klover PJ, Clementi AH, Mooney RA.
Interleukin-6 depletion selectively improves hepatic insulin action in obesity.
Endocrinology.
2005;
146
3417-3427
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 22
Yang R, Barouch LA.
Leptin signaling and obesity: cardiovascular consequences.
Circ Res.
2007;
101
545-559
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 40
Lee AH, Scapa EF, Cohen DE, Glimcher LH.
Regulation of hepatic lipogenesis by the transcription factor XBP1.
Science.
2008;
320
1492-1496
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
- 46
Maedler K.
Beta cells in type 2 diabetes - a crucial contribution to pathogenesis.
Diabetes Obes Metab.
2008;
10
408-420
Reference Ris Wihthout Link
- 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
Reference Ris Wihthout Link
Correspondence
M. NiessenPhD
Ramistraße 100
8091 Zürich
Switzerland
Phone: +41/44/255 2225
Fax: +41/44/255 9741
Email: markus.niessen@usz.ch