Increased Activation of the Mammalian Target of Rapamycin Pathway in Liver and Skeletal Muscle of Obese Rats: Possible Involvement in Obesity-Linked Insulin Resistance

Khamzina, Leila; Veilleux, Alain; Bergeron, Sébastien; Marette, André

doi:10.1210/en.2004-0921

Cited by 562PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic Diseases

Increased Activation of the Mammalian Target of Rapamycin Pathway in Liver and Skeletal Muscle of Obese Rats: Possible Involvement in Obesity-Linked Insulin Resistance

Khamzina, Leila, Veilleux, Alain, Bergeron, Sébastien, Marette, André·2005·Endocrinology

DOI 10.1210/en.2004-0921

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Abstract

The mammalian target of rapamycin (mTOR) pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies also suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol 3-kinase/Akt in adipose and muscle cells. However, it is still unclear whether activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance. In this paper we show that basal (fasting state) activation of mTOR and its downstream target S6K1 is markedly elevated in liver and skeletal muscle of obese rats fed a high fat diet compared with chow-fed, lean controls. Time-course studies also revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation. The relationship between mTOR/S6K1 overactivation and impaired insulin signaling to Akt was also examined in hepatic cells in vitro. Insulin caused a time-dependent activation of mTOR and S6K1 in HepG2 cells. This was associated with increased IRS-1 phosphorylation on Ser636/Ser639. Inhibition of mTOR/S6K1 by rapamycin blunted insulininduced Ser636/Ser639 phosphorylation of IRS-1, leading to a rapid (∼5 min) and persistent increase in IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. These results show that activation of the mTOR pathway is increased in liver and muscle of high fat-fed obese rats. In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity.

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Obese and type 2 diabetic rodents have increased mTOR/S6K signaling.
“Obese and type 2 diabetic rodents have increased mTOR/S6K signaling and this may contribute to insulin resistance [151-153].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [152]

A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359 · see citing works
Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Davies, S., Reddy, H., Caivano, M., & Cohen, P. (2000) · Biochemical Journal · doi:10.1042/bj3510095 · Cited by 3,164 · see citing works
TOR, a central controller of cell growth.
Schmelzle, T., & Hall, M. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 2,044 · see citing works
Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of <i>Ikkβ</i>
Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z.-W., Karin, M., & Shoelson, S. E. (2001) · Science · doi:10.1126/science.1061620 · Cited by 1,884 · see citing works
Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ)
Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., & Birnbaum, M. J. (2001) · Science · doi:10.1126/science.292.5522.1728 · Cited by 1,837 · see citing works
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677 · see citing works
Specificity and mechanism of action of some commonly used protein kinase inhibitors
Davies, S., Reddy, H., Caivano, M., & Cohen, P. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3510095 · Cited by 1,618 · see citing works
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1432 · Cited by 1,139 · see citing works
The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins
Harrington, L. S., Findlay, G. M., Gray, A., Толкачева, Т. А., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403069 · Cited by 1,123 · see citing works
Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action
Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., & White, M. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m101521200 · Cited by 1,010 · see citing works
Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation.
Navé, B., Ouwens, M., Withers, D., Alessi, D. R., & Shepherd, P. (1999) · Biochemical Journal · doi:10.1042/bj3440427 · Cited by 972 · see citing works
A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells.
Sekulić, A., Hudson, C. C., Homme, J. L., Yin, P., Otterness, D. M., Karnitz, L. M., & Abraham, R. T. (2000) · PubMed · Cited by 712 · see citing works
The target of rapamycin (TOR) proteins
Raught, B., Gingras, A., & Sonenberg, N. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.121145898 · Cited by 670 · see citing works
Amino Acid and Insulin Signaling via the mTOR/p70 S6 Kinase Pathway
Tremblay, F., & Marette, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106703200 · Cited by 536 · see citing works
Self-citation
Regulation of eIF-4E BP1 Phosphorylation by mTOR
Hara, K., Yonezawa, K., Kozlowski, M. T., Sugimoto, T., Andrabi, K. I., Weng, Q.-P., Kasuga, M., Nishimoto, I., & Avruch, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.42.26457 · Cited by 529 · see citing works
Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway
Scott, P., Brunn, G. J., Kohn, A. D., Roth, R. A., & Lawrence, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7772 · Cited by 479 · see citing works
A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1.
Haruta, T., Uno, T., Kawahara, J., Takano, A., Egawa, K., Sharma, P. M., Olefsky, J., & Kobayashi, M. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.6.0446 · Cited by 437 · see citing works
A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1
Özeş, O. N., Akça, H., Mayo, L. D., Gustin, J. A., Maehama, T., Dixon, J. E., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051042298 · Cited by 383 · see citing works
The TOR Kinases Link Nutrient Sensing to Cell Growth
Rohde, J. R., Heitman, J., & Cardenas, M. E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r000034200 · Cited by 352 · see citing works
Immunopurified Mammalian Target of Rapamycin Phosphorylates and Activates p70 S6 Kinase α in Vitro
Isotani, S., Hara, K., Tokunaga, C., Inoue, H., Avruch, J., & Yonezawa, K. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.48.34493 · Cited by 337 · see citing works
Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes
Bouzakri, K., Roques, M., Gual, P., Espinosa, S., Guebre-Egziabher, F., Riou, J.-P., Laville, M., Le Marchand-Brustel, Y., Tanti, J.-F., & Vidal, H. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1319 · Cited by 305 · see citing works
Control of Ser2448 Phosphorylation in the Mammalian Target of Rapamycin by Insulin and Skeletal Muscle Load
Reynolds, T., Bodine, S. C., & Lawrence, J. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201142200 · Cited by 272 · see citing works
Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases
Gao, Z., Zuberi, A. R., Quon, M. J., Dong, Z., & Ye, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300423200 · Cited by 258 · see citing works
Phosphorylation of Insulin Receptor Substrate-1 on Multiple Serine Residues, 612, 632, 662, and 731, Modulates Insulin Action
Mothe‐Satney, I., & OBBERGHEN, E. V. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.19.11222 · Cited by 255 · see citing works
Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin
Takano, A., Usui, I., Haruta, T., Kawahara, J., Uno, T., Iwata, M., & Kobayashi, M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.15.5050-5062.2001 · Cited by 249 · see citing works
Splanchnic glucose and amino acid metabolism in obesity.
Felig, P., Wahren, J., Hendler, R., & Brundin, T. (1974) · Journal of Clinical Investigation · doi:10.1172/jci107593 · Cited by 208 · see citing works
Modulation of Insulin Receptor Substrate-1 Tyrosine Phosphorylation by an Akt/Phosphatidylinositol 3-Kinase Pathway
Li, J., DeFea, K., & Roth, R. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.14.9351 · Cited by 196 · see citing works
Integration of Growth Factor and Nutrient Signaling
Shamji, A. F., Nghiem, P., & Schreiber, S. L. (2003) · Molecular Cell · doi:10.1016/j.molcel.2003.08.016 · Cited by 186 · see citing works
The Mammalian Target of Rapamycin Phosphorylates Sites Having a (Ser/Thr)-Pro Motif and Is Activated by Antibodies to a Region near Its COOH Terminus
Brunn, G. J., Fadden, P., Haystead, T., & Lawrence, J. C. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.51.32547 · Cited by 168 · see citing works
Tyr612 and Tyr632 in Human Insulin Receptor Substrate-1 Are Important for Full Activation of Insulin-Stimulated Phosphatidylinositol 3-Kinase Activity and Translocation of GLUT4 in Adipose Cells
Esposito, D. L., Li, Y., Cama, A., & Quon, M. J. (2001) · Endocrinology · doi:10.1210/endo.142.7.8283 · Cited by 161 · see citing works
Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats
Lavigne, C., Tremblay, F., Asselin, G., Jacques, H., & Marette, A. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.1.e62 · Cited by 161 · see citing works
Self-citation
Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation
Carlson, C. J., White, M. F., & Rondinone, C. M. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.02.082 · Cited by 155 · see citing works
MAP kinases and mTOR mediate insulin-induced phosphorylation of Insulin Receptor Substrate-1 on serine residues 307, 612 and 632
Gual, P., Grémeaux, T., Gonzalez, T., MARCHAND‐BRUSTEL, Y. L., & Tanti, J. (2003) · Diabetologia · doi:10.1007/s00125-003-1223-4 · Cited by 144 · see citing works
Identification of Enhanced Serine Kinase Activity in Insulin Resistance
Qiao, L. Y., Goldberg, J. L., Russell, J. C., & Sun, X. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.15.10625 · Cited by 111 · see citing works
In Vivo Phosphorylation of Insulin Receptor Substrate 1 at Serine 789 by a Novel Serine Kinase in Insulin-resistant Rodents
Qiao, L.-Y., Zhande, R., Jetton, T. L., Zhou, G., & Sun, X. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201494200 · Cited by 104 · see citing works
Role of Ser/Thr kinases in the uncoupling of insulin signaling
Zick, Y. (2003) · International Journal of Obesity · doi:10.1038/sj.ijo.0802503 · Cited by 94 · see citing works
Rapamycin partially prevents insulin resistance induced by chronic insulin treatment
Berg, C. E., Lavan, B. E., & Rondinone, C. M. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00333-9 · Cited by 68 · see citing works
Signalling pathways involved in the stimulation of glycogen synthesis by insulin in rat hepatocytes
Peak, M., Rochford, J. J., Borthwick, A. C., Yeaman, S. J., & Agius, L. (1998) · Diabetologia · doi:10.1007/s001250050861 · Cited by 57 · see citing works
In Rat Hepatocytes Glucagon Increases Mammalian Target of Rapamycin Phosphorylation on Serine 2448 but Antagonizes the Phosphorylation of Its Downstream Targets Induced by Insulin and Amino Acids
Mothe‐Satney, I., Gautier, N., Hinault, C., Lawrence, J. C., & OBBERGHEN, E. V. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405173200 · Cited by 53 · see citing works
Insulin Stimulation of Mitogen-activated Protein Kinase, p90 , and p70 S6 Kinase in Skeletal Muscle of Normal and Insulin-resistant Mice
Chang, P.-Y., MARCHAND‐BRUSTEL, Y. L., Cheatham, L. A., & Moller, D. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.50.29928 · Cited by 48 · see citing works

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Hotamisligil, G. S. (2010) · Cell · doi:10.1016/j.cell.2010.02.034 · Cited by 2,802 · see citing works
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Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., & Seeley, R. J. (2006) · Science · doi:10.1126/science.1124147 · Cited by 1,278 · see citing works
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Copps, K. D., & White, M. F. (2012) · Diabetologia · doi:10.1007/s00125-012-2644-8 · Cited by 1,017 · see citing works
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Gregor, M. F., & Hotamisligil, G. S. (2007) · Journal of Lipid Research · doi:10.1194/jlr.r700007-jlr200 · Cited by 586 · see citing works
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Tremblay, F., Brûlé, S., Hee Um, S., Li, Y., Masuda, K., Roden, M., Sun, X. J., Krebs, M., Polakiewicz, R. D., Thomas, G., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706517104 · Cited by 465 · see citing works
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Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436 · see citing works
Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation
Tanti, J.-F., & Jager, J. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.004 · Cited by 430 · see citing works
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Authors: Khamzina, L., Veilleux, A., Bergeron, S., & Marette, A.
Affiliations: Université Laval (CA)
ORCID: Veilleux, Alain
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2005-03-01
Volume: 146
Issue: 3
Pages: 1473-1481
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2004-0921
OpenAlex: W1967257827
Cited by: 562
References: 40
Citations by year: 2026: 10 · 2025: 20 · 2024: 26 · 2023: 13 · 2022: 25 · 2021: 31 · 2020: 28 · 2019: 26 · 2018: 33 · 2017: 27 · 2016: 28 · 2015: 34 · 2014: 33 · 2013: 28 · 2012: 44
FWCI: 4.85
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: mTOR signaling, S6K1, insulin resistance, obesity, high-fat diet, liver, skeletal muscle, IRS-1 serine phosphorylation, Akt signaling, phosphatidylinositol 3-kinase, rapamycin, insulin signaling, hepatic insulin signaling
MeSH terms: Animals, Cell Line, Disease Models, Animal, Enzyme Activation, Food Deprivation, Humans, Insulin, Insulin Resistance, Liver, Male, Muscles, Obesity, Phosphorylation, Protein Kinases, Proto-Oncogene Proteins, Serine, Time Factors, Immunoblotting, Signal Transduction, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, 70-kDa, Immunoprecipitation, Proto-Oncogene Proteins c-akt, Rats, TOR Serine-Threonine Kinases

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Increased Activation of the Mammalian Target of Rapamycin Pathway in Liver and Skeletal Muscle of Obese Rats: Possible Involvement in Obesity-Linked Insulin Resistance

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