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Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss
Open accessAbstract
OBJECTIVE: Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS: Eleven obese men and women (BMI 51.3 +/- 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers. RESULTS: Subjects lost 39 +/- 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2alpha (eIF2alpha) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2alpha before surgery, which was reduced in post-GBP sections. CONCLUSIONS: This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.
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“Substantial weight loss in patients after bariatric surgery has also been associated with both improvements in insulin sensitivity and reduction in markers of endoplasmic-reticulum stress.132”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [132]
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Cites
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199 · cited 1×
“In the past decade, it was recognized and established that chronic inflammatory and stress responses are a central feature of obesity, insulin resistance, and type 2 diabetes and contribute to the metabolic imbalance (4).”
BackgroundSignal integration in the endoplasmic reticulum unfolded protein response
Ron, D., & Walter, P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2199 · Cited by 6,431 · cited 1×
“The UPR is initiated by three ER transmembrane sensors (namely PERK (PKR-like ER-regulated kinase), IRE-1 (inositolrequiring enzyme-1), and ATF-6 (activating transcription factor-6) which activate an adaptive response that results in cessation of protein translation and transcriptional increase in proteinfolding chape…”
BackgroundMatsuda, M., & DeFronzo, R. A. (1999) · Diabetes Care · doi:10.2337/diacare.22.9.1462 · Cited by 5,621
Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects
Sjöström, L., Narbro, K., Sjöström, C. D., Karason, K., Larsson, B., Wedel, H., Lystig, T., Sullivan, M., Bouchard, C., Carlsson, B., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa066254 · Cited by 4,668 · cited 1×
“Weight loss induced by GBP surgery improves or completely resolves most obesity-related medical complications and increases survival [24, 25].”
BackgroundEndoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844 · cited 3×
“Data obtained from mouse models demonstrate that genetically compromised ER folding capacity induces ER stress, activates JNK, and leads to whole-body insulin resistance in the mouse (7).”
BackgroundInfluentialUrano, F., Wang, X.-Z., Bertolotti, A., Zhang, Y.-H., Chung, P., Harding, H., & Ron, D. (2000) · Science · doi:10.1126/science.287.5453.664 · Cited by 3,081 · cited 2×
“The UPR is also able to induce activation of the c-Jun NH2-terminal kinase (JNK) pathway and thereby inhibit insulin signaling through the subsequent phosphorylation and/or degradation of IRS1 (7–9).”
BackgroundÖzcan, U., Yilmaz, E., Özcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O., Görgün, C. Z., & Hotamisligil, G. S. (2006) · Science · doi:10.1126/science.1128294 · Cited by 2,413 · cited 1×
“In contrast, enhancing ER capacity in obese mice through the use of chemical or molecular chaperones relieves ER stress in adipose tissue and liver, reduces intrahepatic fat accumulation, and restores glucose homeostasis (10).”
BackgroundObesity and Diabetes in the Developing World — A Growing Challenge
Hossain, P., Kawar, B., & El Nahas, M. (2007) · New England Journal of Medicine · doi:10.1056/nejmp068177 · Cited by 2,200
Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-α,in Vivo1
Mohamed‐Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., & Coppack, S. W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4450 · Cited by 2,032
Kern, P. A., Ranganathan, S., Li, C., Wood, L., & Ranganathan, G. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e745 · Cited by 1,883 · cited 1×
“Earlier studies have shown that IL-6 expression is significantly and consistently down-regulated in adipose tissue after weight loss [17-21].”
Background
Flagged first, then by citations
1 of the 29 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802
“Finally, we showed that when obese patients undergo marked weight loss due to gastric by-pass surgery, there is a decrease in ER stress markers in liver and adipose tissue (Gregor et al., 2009).”
DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel, V. T., & Shulman, G. I. (2012) · Cell · doi:10.1016/j.cell.2012.02.017 · Cited by 2,294
“Further, markers of the UPR are decreased after surgical induced weight loss (Gregor et al., 2009).”
Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications
Fabbrini, E., Sullivan, S., & Klein, S. (2010) · Hepatology · doi:10.1002/hep.23280 · Cited by 2,100
Lipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189
Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes
Zatterale, F., Longo, M., Naderi, J., Raciti, G. A., Desiderio, A., Miele, C., & Beguinot, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2019.01607 · Cited by 1,180
“Several studies have shown that the incorrect functioning of the UPR (i.e., ER-stress mitigation system in eukaryotes) is associated with chronic metabolic diseases including obesity, IR, and T2D (Ozcan et al., 2006; Boden et al., 2008; Sharma et al., 2008; Gregor et al., 2009).”
BackgroundEndoplasmic reticulum stress in liver disease
Malhi, H., & Kaufman, R. J. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.11.005 · Cited by 1,195
Adipose tissue and insulin resistance in obese
Ahmed, B., Sultana, R., & Greene, M. W. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111315 · Cited by 1,144
Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L. H., Hide, W. A., Lin, X., Watkins, S. M., Ivanov, A. R., & Hotamışlıgil, G. S. (2011) · Nature · doi:10.1038/nature09968 · Cited by 1,045
Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease
Lebeaupin, C., Vallée, D., Hazari, Y., Hetz, C. A., Chevet, É., & Bailly‐Maitre, B. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.06.008 · Cited by 971
“reduced hepatic lipid content after bariatric surgery (54).”
BackgroundAMPK, insulin resistance, and the metabolic syndrome
Ruderman, N. B., Carling, D., Prentki, M., & Cacicedo, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67227 · Cited by 886
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training
Roberts, C. K., Hevener, A. L., & Barnard, R. J. (2012) · Comprehensive physiology · doi:10.1002/cphy.c110062 · Cited by 966
Arruda, A. P., Pers, B. M., Parlakgül, G., Güney, E., Inouye, K., & Hotamışlıgil, G. S. (2014) · Nature Medicine · doi:10.1038/nm.3735 · Cited by 741
Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease
Softic, S., Cohen, D. E., & Kahn, C. R. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4054-0 · Cited by 709
“Likewise, XBP1s has been shown to be elevated in liver biopsies from obese subjects undergoing bariatric surgery and declines following weight loss [127].”
BackgroundEndoplasmic reticulum stress, obesity and diabetes
Cnop, M., Foufelle, F., & Velloso, L. A. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.07.010 · Cited by 705
Volmer, R., van der Ploeg, K., & Ron, D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217611110 · Cited by 668
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro, N., Erion, D. M., Zhang, D., Kahn, M., Beddow, S. A., Chu, X., Still, C. D., Gerhard, G. S., Han, X., Dziura, J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113359108 · Cited by 585
“Activation of the unfolded protein response, or ER stress pathway, has also been implicated to cause hepatic insulin resistance (16, 34).”
BackgroundThe Role of Endoplasmic Reticulum in Hepatic Lipid Homeostasis and Stress Signaling
Fu, S., Watkins, S. M., & Hotamışlıgil, G. S. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.03.007 · Cited by 554
Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association
Bays, H. E., Toth, P. P., Kris-Etherton, P. M., Abate, N., Aronne, L. J., Brown, W. V., Gonzalez-Campoy, J. M., Jones, S. R., Kumar, R., La Forge, R., et al. (2013) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2013.04.001 · Cited by 521
“Activation of the UPR in livers of leptin-deficient ob/ob mice(52) suggests that these pathways may be involved in the pathogenesis of insulin resistance in obese states in rodents as well as in humans.(53) Chemical inducers of the UPR impaired insulin signaling,(52) whereas chemical chaperones that reduce ER stress i…”
BackgroundNakamura, T., Furuhashi, M., Li, P., Cao, H., Tuncman, G., Sonenberg, N., Görgün, C. Z., & Hotamışlıgil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.01.001 · Cited by 512
“In both mouse and human, there is a consistent and marked increase in phosphorylation of eIF2a and JNK activity in obese metabolic tissues (Gregor et al., 2009).”
BackgroundInsulin Resistance, Obesity and Lipotoxicity
Yazıcı, D., & Sezer, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-48382-5_12 · Cited by 525
Cell Signaling and Stress ResponsesPreprint
Hotamışlıgil, G. S., & Davis, R. J. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a006072 · Cited by 512
“…cause ER dysfunction and/or stress in animal models (Ozcan et al. 2004; Nakatani et al. 2005) and humans (Boden et al. 2008; Sharma et al. 2008; Gregor et al. 2009), and chemicals that reduce ER stress and improve ER function improve glucose metabolism in animal models (Ozawa et al. 2005;…”
BackgroundErtunc, M. E., & Hotamışlıgil, G. S. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r066514 · Cited by 500
Erbay, E., Babaev, V. R., Mayers, J. R., Makowski, L., Charles, K. N., Snitow, M. E., Fazio, S., Wiest, M. M., Watkins, S. M., Linton, M. F., et al. (2009) · Nature Medicine · doi:10.1038/nm.2067 · Cited by 490
“To detect macrophages in arterial lesions, we fixed 5-μm serial cryosections of the proximal aorta in acetone and incubated them with antibodies following the manufacturer's recommendations and previously established protocol”
MethodHepatocyte Death: A Clear and Present Danger
Malhi, H., Guicciardi, M. E., & Gores, G. J. (2010) · Physiological Reviews · doi:10.1152/physrev.00061.2009 · Cited by 477
Role of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders
Özcan, L., & Tabas, I. A. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-043010-144749 · Cited by 468
Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2017 · Cited by 462
“In obese individuals, gastric bypass surgery-mediated weight loss, as well as physical exercise, have been shown to attenuate SAT ER stress, which were associated with improved insulin sensitivity (86, 146).”
BackgroundPathology of nonalcoholic fatty liver disease
Brunt, E. M. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.21 · Cited by 484
Endoplasmic Reticulum Stress and Inflammation in Obesity and Diabetes
Hummasti, S., & Hotamışlıgil, G. S. (2010) · Circulation Research · doi:10.1161/circresaha.110.225698 · Cited by 445
Leamy, A. K., Egnatchik, R. A., & Young, J. D. (2012) · Progress in Lipid Research · doi:10.1016/j.plipres.2012.10.004 · Cited by 424
“Clinical studies of patients suffering from metabolic syndrome disorders, such as NAFLD, have increased levels of ER stress markers in the liver and other tissues [37] [38] [39].”
Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T., Finck, B. N., Patterson, B. W., Horton, J. D., Mittendorfer, B., Hotamışlıgil, G. S., et al. (2010) · Diabetes · doi:10.2337/db10-0308 · Cited by 409
“Increased ER stress in liver and adipose tissue and insulin resistance are also associated with obesity in humans (22,23), whereas weight loss decreases ER stress and improves insulin sensitivity (22).”
BackgroundMethodInfluentialER stress induces NLRP3 inflammasome activation and hepatocyte death
Lebeaupin, C., Proïcs, E., de Bieville, C.-H. D., Rousseau, D., Bonnafous, S., Patouraux, S., Adam, G., Lavallard, V., Rovère, C., Thuc, O. L., et al. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.248 · Cited by 409
“Increased activation of the ER stress response has been reported in obese mice and humans.(3,4,7,8) Obesity results in liver ER stress, which promotes insulin resistance and hepatosteatosis through the IRE1α branch.”
BackgroundNASH is an Infl ammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications
Farrell, G. C., Rooyen, D. M. V., Gan, L. T., & Chitturi, S. (2012) · Gut and Liver · doi:10.5009/gnl.2012.6.2.149 · Cited by 408
Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Peverill, W., Powell, L. W., & Skoien, R. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058591 · Cited by 387
“As mentioned earlier, ER stress contributes to disease progression and it has been shown that saturated FFAs directly induce a hepatocyte ER stress response[111], with increased levels of ER stress seen in patients with NAFLD/NASH [112,113].”
BackgroundThe contribution of endoplasmic reticulum stress to liver diseases
Dara, L., Ji, C., & Kaplowitz, N. (2011) · Hepatology · doi:10.1002/hep.24279 · Cited by 373
Shan, B., Wang, X., Wu, Y., Xu, C., Xia, Z., Dai, J., Shao, M., Zhao, F., He, S., Yang, L., et al. (2017) · Nature Immunology · doi:10.1038/ni.3709 · Cited by 367
Apoptosis and Necrosis in the Liver
Guicciardi, M. E., Malhi, H., Mott, J. L., & Gores, G. J. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120020 · Cited by 403
“UPR pathways are activated in the livers of obese patients (120).”
Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer's disease
Ferreira, S. T., Clarke, J. R., Bomfim, T. R., & Felice, F. G. D. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.12.010 · Cited by 363
“[40] Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, Hotamisligil GS, et al.”
Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy
Schönthal, A. H. (2012) · Scientifica · doi:10.6064/2012/857516 · Cited by 357
Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes
Arruda, A. P., & Hotamışlıgil, G. S. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.010 · Cited by 352
“In obesity, both in experimental models and in humans, there is significantly increased JNK activity in adipose tissue, which has significant metabolic consequences (Boden et al., 2008; Gregor et al., 2009; Tobar et al., 2011; Tsukumo et al., 2007).”
BackgroundThe critical role of GRP78 in physiologic and pathologic stress
Pfaffenbach, K. T., & Lee, A. S. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.09.007 · Cited by 333
“GRP78 mRNA was decreased in adipose tissue of gastric bypass patients after weight loss, implying that the relationship between obesity-related ER stress and metabolism dysfunction exists in humans as well [24].”
BackgroundA vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease
Chen, Z., Yu, R., Xiong, Y., Du, F.-T., & Zhu, S. (2017) · Lipids in Health and Disease · doi:10.1186/s12944-017-0572-9 · Cited by 325
Ashraf, N. U., & Sheikh, T. A. (2015) · Free Radical Research · doi:10.3109/10715762.2015.1078461 · Cited by 312
“Increasing evidences report positive eff ects of herbal medicines and natural products on NAFLD/NASH in animal models of the disease.”
BackgroundInfluentialNew insights into ER stress-induced insulin resistance
Flamment, M., Hajduch, E., Ferré, P., & Foufelle, F. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.06.003 · Cited by 306
The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes
Cusi, K. J. (2010) · Current Diabetes Reports · doi:10.1007/s11892-010-0122-6 · Cited by 311
“Weight loss can reverse these abnormalities [ 13 ].”
BackgroundLi, Y., Xu, S., Giles, A. J., Nakamura, K., Lee, J. W., Hou, X., Dönmez, G., Li, J., Luo, Z., Walsh, K. X., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-173492 · Cited by 305
“Because of the limited availability of antibodies that recognize phosphorylated forms of human endogenous PERK and IRE-1 , two major proximal sensors of the UPR pathway (7), phosphorylation of eIF2 at Ser51, which could be mediated by PERK activation, was assessed.”
BackgroundResultRole of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease
Zhang, X.-Q. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i7.1768 · Cited by 302
Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
Holzer, R. G., Park, E., Li, N., Tran, H., Chen, M. F., Choi, C., Solinas, G., & Karin, M. (2011) · Cell · doi:10.1016/j.cell.2011.08.034 · Cited by 283
“JNK activity is elevated in adipocytes of obese individuals (Gregor et al., 2009) and mice (Hirosumi et al.”
Insulin resistance and insulin sensitizing agents
Mastrototaro, L., & Roden, M. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154892 · Cited by 274
Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential
Basseri, S., & Austin, R. C. (2011) · Biochemistry Research International · doi:10.1155/2012/841362 · Cited by 265
“Gastric bypass surgery-mediated weight loss in obese patients was effective at reducing ER stress in adipose and liver tissues and improved insulin sensitivity [16].”
BackgroundEngin, F., & Hotamışlıgil, G. S. (2010) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2010.01282.x · Cited by 241
“Liver biopsies from a subset of four patients also showed reduced staining for GRP78 and phospho-eIF2α proteins, suggesting reduced nutrient intake and subsequently reduced adiposity resulted in decreased ER stress in humans [49].”
BackgroundGastric bypass and banding equally improve insulin sensitivity and β cell function
Bradley, D., Conte, C., Mittendorfer, B., Eagon, J. C., Varela, J. E., Fabbrini, E., Gastaldelli, A., Chambers, K. T., Su, X., Okunade, A., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci64895 · Cited by 244
Self-citationLipid-dependent regulation of the unfolded protein response
Volmer, R., & Ron, D. (2014) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2014.12.002 · Cited by 241
“Increased UPR markers have also been observed in the liver and adipose tissue of mice fed a high fat diet and in severely obese humans [14,15].”
BackgroundThe Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 236
Developmental origins of NAFLD: a womb with a clue
Wesolowski, S. R., Kasmi, K. C. E., Jonscher, K. R., & Friedman, J. E. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.160 · Cited by 239
Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences.
van Greevenbroek, M. M. J., Schalkwijk, C., & Stehouwer, C. D. A. (2013) · PubMed · Cited by 233
Basseri, S., Lhoták, Š., Sharma, A. M., & Austin, R. C. (2009) · Journal of Lipid Research · doi:10.1194/jlr.m900216-jlr200 · Cited by 228
The role of declining adaptive homeostasis in ageing
Pomatto, L. C. D., & Davies, K. J. A. (2017) · The Journal of Physiology · doi:10.1113/jp275072 · Cited by 231
“The relationship between GRPs and metabolic disorders appears to be conserved in humans, as patients who underwent gastric bypass surgery showed a decline in ER stress within adipose tissue 1 year after the surgery, including decreased levels of adipose GRP78 expression (Gregor et al. 2009).”
BackgroundEndoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease
Pagliassotti, M. J. (2012) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071811-150644 · Cited by 222
Targeting endoplasmic reticulum stress in insulin resistance
Salvadó, L., Palomer, X., Barroso, E., & Vázquez‐Carrera, M. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.05.007 · Cited by 219
Endoplasmic reticulum proteostasis in hepatic steatosis
Baiceanu, A., Mesdom, P., Lagouge, M., & Foufelle, F. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.124 · Cited by 216
Mechanisms of Lipotoxicity in NAFLD and Clinical Implications
Ibrahim, S. H., Kohli, R., & Gores, G. J. (2011) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e31822578db · Cited by 207
Xiao, C., Giacca, A., & Lewis, G. F. (2011) · Diabetes · doi:10.2337/db10-1433 · Cited by 198
“Furthermore, gastric bypass surgery in obese patients is associated with reduced ER stress in adipose tissues along with weight loss and improved insulin sensitivity (30).”
BackgroundChildhood Obesity and Environmental Chemicals
Merrill, M. A. L., & Birnbaum, L. S. (2011) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20229 · Cited by 195
Winnay, J. N., Boucher, J., Mori, M. A., Ueki, K., & Kahn, C. R. (2010) · Nature Medicine · doi:10.1038/nm.2121 · Cited by 195
“Conversely, the increase in insulin sensitivity associated with weight loss is associated with a substantial reduction in markers of UPR activatio”
Hepatic Steatosis as a Marker of Metabolic Dysfunction
Fabbrini, E., & Magkos, F. (2015) · Nutrients · doi:10.3390/nu7064995 · Cited by 192
“The putative role of endoplasmic reticulum stress in mediating steatosis and hepatic insulin resistance is supported by the observations that ER-stress is increased in the liver of obese subjects with NAFLD [56], and decreases with weight loss, concomitant to an improvement in hepatic insulin sensitivity and the resol…”
Backgroundİnceoğlu, B., Bettaieb, A., Trindade‐da‐Silva, C. A., Lee, K. S. S., Haj, F. G., & Hammock, B. D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510137112 · Cited by 184
Jiang, S., Cheng, Y., Fang, Q., Shao, M., Zhang, Y., Liu, Y., Deng, Y., Shan, B., Liu, J., Li, H., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.565960 · Cited by 182
Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes
Legrand-Poels, S., Esser, N., L’homme, L., Scheen, A., Paquot, N., & Piette, J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.08.013 · Cited by 194
Liu, J., Zhou, L., Xiong, K., Godlewski, G., Mukhopadhyay, B., Tam, J., Yin, S., Gao, P., Shan, X., Pickel, J. M., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.01.032 · Cited by 175
Pathophysiology of Non Alcoholic Fatty Liver Disease
Petta, S., Gastaldelli, A., Rebelos, E., Bugianesi, E., Messa, P., Miele, L., Svegliati‐Baroni, G., Valenti, L. V. C., & Bonino, F. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122082 · Cited by 182
“Fetuin-A could affect NAFLD/NASH because it is implicated in the development of insulin resistance and accelerated atherogenesis associated with fatty liver [199,201].”
BackgroundInfluentialPiperi, C., Adamopoulos, C., Dalagiorgou, G., Diamanti‐Kandarakis, E., & Papavassiliou, A. G. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3408 · Cited by 169
“ER stress may also induce SREBP activation and thus regulate the transcription of target genes involved in lipid synthesis (SREBP1c) or cholesterol metabolism (SREBP1a, SREBP2) (52).”
BackgroundPathophysiology of NASH: perspectives for a targeted treatment
Marra, F., & Lotersztajn, S. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990344 · Cited by 163
Gariani, K., Ryu, D., Menzies, K. J., Yi, H.-S., Stein, S., Zhang, H., Perino, A., Lemos, V., Katsyuba, E., Jha, P., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2016.08.024 · Cited by 167
Effects of Bariatric Surgery on Glucose Homeostasis and Type 2 Diabetes
Bradley, D. P., Magkos, F., & Klein, S. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.07.114 · Cited by 154
Endoplasmic Reticulum Stress in Metabolic Liver Diseases and Hepatic Fibrosis
Maiers, J. L., & Malhi, H. (2019) · Seminars in Liver Disease · doi:10.1055/s-0039-1681032 · Cited by 151
Gambino, R., Musso, G., & Cassader, M. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3058 · Cited by 147
“(90) provided evidence of activation of ER stress in the liver and adipose tissue of obese patients undergoing bariatric surgery.”
Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease
Huang, S., Xing, Y., & Liu, Y. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.007036 · Cited by 152
“Increased ER stress signaling in white adipose tissue has been described in both animal models and human patients with obesity and diabetes (22, 48, 116), and emerging evidence from studies of XBP1 in adipocytes and IRE1 in ATMs suggests that IRE1 signaling is critically involved in the regulation of adipose tissue in…”
BackgroundRole of Lipotoxicity in Endothelial Dysfunction
Kim, J., Montagnani, M., Chandrasekran, S., & Quon, M. J. (2012) · Heart Failure Clinics · doi:10.1016/j.hfc.2012.06.012 · Cited by 153
Özcan, L., de Souza, J. C., Harari, A. A., Backs, J., Olson, E. N., & Tabas, I. A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.011 · Cited by 145
“Because hepatic ER stress is increased obesity and may act as a link between obesity and insulin resistance (Gregor et al., 2009; Ozcan 810 Cell Metabolism 18, 803–815, December 3, 2013 a2013 Elsevier et al., 2004), we reasoned that a CaMKII-ATF4-TRB3 pathway might be upstream of defective insulin-induced p-Akt in obe…”
BackgroundYahoo, N., Dudek, M., Knolle, P. A., & Heikenwälder, M. F. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.02.033 · Cited by 147
Usui, M., Yamaguchi, S., Tanji, Y., Tominaga, R., Ishigaki, Y., Fukumoto, M., Katagiri, H., Mori, K., Oka, Y., & Ishihara, H. (2012) · Metabolism · doi:10.1016/j.metabol.2012.01.004 · Cited by 143
Niederreiter, L., Fritz, T. M. J., Adolph, T. E., Krismer, A.-M., Offner, F. A., Tschurtschenthaler, M., Flak, M. B., Hosomi, S., Tomczak, M. F., Kaneider, N. C., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20122341 · Cited by 145
“ER stress in various organs, including the liver, skeletal muscle, adipose tissue (Ozcan et al., 2004; Gregor et al., 2009; Kars et al., 2010), and intestinal crypts (Hodin et al.”
BackgroundPrattichizzo, F., De Nigris, V., La Sala, L., Procopio, A. D., Olivieri, F., & Ceriello, A. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1810327 · Cited by 129
“UPR markers are overexpressed in the liver and adipose tissue of diabetic rodents [113] as well as in ex vivo samples from T2DM patients [114].”
BackgroundEndoplasmic reticulum stress in obesity and obesity-related disorders: An expanded view
Pagliassotti, M. J., Kim, P., Estrada, A. L., Stewart, C. M., & Gentile, C. L. (2016) · Metabolism · doi:10.1016/j.metabol.2016.05.002 · Cited by 137
“The ratio of monounsaturated to saturated fatty acids has been shown to play a role in both the activation of the UPR in the liver and liver damage in rodent models of NAFLD [4, 83].”
BackgroundInfluentialBettaieb, A., Prieto, M. A. V., Lanzi, C. R., Miatello, R. M., Haj, F. G., Fraga, C. G., & Oteiza, P. I. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.04.011 · Cited by 135
Role of macrophage tissue infiltration in obesity and insulin resistance
Bourlier, V., & Bouloumié, A. (2009) · Diabetes & Metabolism · doi:10.1016/j.diabet.2009.05.001 · Cited by 141
The Role of Lipid and Lipoprotein Metabolism in Non‐Alcoholic Fatty Liver Disease
Perla, F. M., Prelati, M., Lavorato, M., Visicchio, D., & Anania, C. (2017) · Children · doi:10.3390/children4060046 · Cited by 144
“It is known that ER stress is increased in the liver of obese individuals with NAFLD [34], and decreased in those with weight loss in parallel with an improvement in hepatic insulin sensitivity and the resolution of steatosis [35].”
BackgroundHepatocytes: A key role in liver inflammation
Gong, J., Tu, W., Liu, J., & Tian, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1083780 · Cited by 152
“ER stress markers are shown to decline in livers of obese patients following weight loss after bariatric surgery (11).”
BackgroundPhysiology and pathophysiology of liver lipid metabolism
Ponziani, F. R., Pecere, S., Gasbarrini, A., & Ojetti, V. (2015) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/17474124.2015.1056156 · Cited by 133
Causes and cures for endoplasmic reticulum stress in lipotoxic β ‐cell dysfunction
Cnop, M., Ladrière, L., Igoillo‐Esteve, M., Moura, R. F., & Cunha, D. A. (2010) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2010.01279.x · Cited by 150
“Increased expression of ER stress markers was detected in fat and liver tissues from obese individuals [47–49].”
BackgroundVillalobos-Labra, R., Subiabre, M., Toledo, F., Pardo, F., & Sobrevía, L. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.11.001 · Cited by 129
Exercise, heat shock proteins and insulin resistance
Archer, A. E., Von Schulze, A. T., & Geiger, P. C. (2018) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2016.0529 · Cited by 122
Metabolic signals and innate immune activation in obesity and exercise
Ringseis, R., Eder, K., Mooren, F. C., & Krüger, K. (2026) · PubMed · doi:10.22029/eir.2015.1696 · Cited by 120
Amaro, A., Fabbrini, E., Kars, M., Yue, P., Schechtman, K. B., Schonfeld, G., & Klein, S. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.03.039 · Cited by 124
Defective regulation of adipose tissue autophagy in obesity
Nuñez, C. E. C., Rodrigues, V. S., Gomes, F. S., de Moura, R. F., Victorio, S. C. D. S., Bombassaro, B., Chaim, É. A., Pareja, J. C., Geloneze, B., Velloso, L. A., et al. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.27 · Cited by 117
Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a–JNK Signaling
Bretón‐Romero, R., Feng, B., HOLBROOK, M. M., Farb, M. G., Fetterman, J. L., Linder, E. A., Berk, B. D., Masaki, N., Weisbrod, R. M., Inagaki, E., et al. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.115.306578 · Cited by 117
The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance
Pál, M., Febbraio, M. A., & Lancaster, G. I. (2015) · The Journal of Physiology · doi:10.1113/jp271457 · Cited by 119
“The Journal of Physiology C© 2015 The Physiological Society JNK levels in subcutaneous abdominal adipose tissue biopsies (Gregor et al. 2009; Carvalho et al. 2013).”
BackgroundNon-alcoholic fatty liver disease and insulin resistance: From bench to bedside
Gariani, K., Philippé, J., & Jornayvaz, F. R. (2012) · Diabetes & Metabolism · doi:10.1016/j.diabet.2012.11.002 · Cited by 113
Metadata
- Authors
- Gregor, M. F., Yang, L., Fabbrini, E., Mohammed, B. S., Eagon, J. C., Hotamisligil, G. S., & Klein, S.
- Affiliations
- Harvard University (US)
- Washington University in St. Louis (US)
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
- Corresponding author
- Klein, Samuel
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2009-03-01
- Volume
- 58
- Issue
- 3
- Pages
- 693-700
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2646068
- OpenAlex
- W2122631753
- Cited by
- 488
- References
- 29
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 16 · 2023: 22 · 2022: 22 · 2021: 22 · 2020: 25 · 2019: 19 · 2018: 28 · 2017: 31 · 2016: 32 · 2015: 47 · 2014: 38 · 2013: 42 · 2012: 43
- FWCI
- 11.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (5t32es007155-24, UL1TR000448)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK52539, DK37948, DK56341, R01DK037948, R01DK052539, P30DK056341, P30DK040561)
- National Institute of Environmental Health Sciences (T32-ES007155, T32 ES007155-24)
- National Center for Research Resources (UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Keywords
- endoplasmic reticulum stress, obesity, weight loss, gastric bypass, insulin resistance, type 2 diabetes, adipose tissue, liver, skeletal muscle, GRP78, eIF2α, JNK1, insulin sensitivity
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Adipose Tissue, Endoplasmic Reticulum, Female, Follow-Up Studies, Humans, Hyperinsulinism, Insulin Resistance, Liver, Male, Middle Aged, Obesity, Stress, Physiological, Glucose Clamp Technique, Gastric Bypass, Muscle, Skeletal
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