Skip to main content

Advertisement

SpringerLink
Log in

Exercise in ZDF rats does not attenuate weight gain, but prevents hyperglycemia concurrent with modulation of amino acid metabolism and AKT/mTOR activation in skeletal muscle

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Protein metabolism is altered in obesity, accompanied by elevated plasma amino acids (AA). Previously, we showed that exercise delayed progression to type 2 diabetes in obese ZDF rats with maintenance of β cell function and reduction in hyperglucocorticoidemia. We hypothesized that exercise would correct the abnormalities we found in circulating AA and other indices of skeletal muscle protein metabolism.

Methods

Male obese prediabetic ZDF rats (7–10/group) were exercised (swimming) 1 h/day, 5 days/week from ages 6–19 weeks, and compared with age-matched obese sedentary and lean ZDF rats.

Results

Food intake and weight gain were unaffected. Protein metabolism was altered in obese rats as evidenced by increased plasma concentrations of essential AA, and increased muscle phosphorylation (ph) of Aktser473 (187 %), mTORser2448 (140 %), eIF4E-binding protein 1 (4E-BP1) (111 %), and decreased formation of 4E-BP1*eIF4E complex (75 %, 0.01 ≤ p ≤ 0.05 for all measures) in obese relative to lean rats. Exercise attenuated the increase in plasma essential AA concentrations and muscle Akt and mTOR phosphorylation. Exercise did not modify phosphorylation of S6K1, S6, and 4E-BP1, nor the formation of 4E-BP1*eIF4E complex, mRNA levels of ubiquitin or the ubiquitin ligase MAFbx. Positive correlations were observed between ph–Akt and fed circulating branched-chain AA (r = 0.56, p = 0.008), postprandial glucose (r = 0.42, p = 0.04) and glucose AUC during an IPGTT (r = 0.44, p = 0.03).

Conclusion

Swimming exercise-induced attenuation of hyperglycemia in ZDF rats is independent of changes in body weight and could result in part from modulation of muscle AKT activation acting via alterations of systemic AA metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chevalier S, Marliss EB, Morais JA, Lamarche M, Gougeon R (2005) Whole-body protein anabolic response is resistant to the action of insulin in obese women. Am J Clin Nutr 82(2):355–365

    CAS  Google Scholar 

  2. Gougeon R, Pencharz PB, Marliss EB (1994) Effect of NIDDM on the kinetics of whole-body protein metabolism. Diabetes 43(2):318–328

    Article  CAS  Google Scholar 

  3. Gougeon R, Styhler K, Morais JA, Jones PJ, Marliss EB (2000) Effects of oral hypoglycemic agents and diet on protein metabolism in type 2 diabetes. Diabetes Care 23(1):1–8

    Article  CAS  Google Scholar 

  4. Chevalier S, Gougeon R, Choong N, Lamarche M, Morais JA (2006) Influence of adiposity in the blunted whole-body protein anabolic response to insulin with aging. J Gerontol A Biol Sci Med Sci 61(2):156–164

    Article  Google Scholar 

  5. Guillet C, Delcourt I, Rance M, Giraudet C, Walrand S, Bedu M, Duche P, Boirie Y (2009) Changes in basal and insulin and amino acid response of whole body and skeletal muscle proteins in obese men. J Clin Endocrinol Metab 94(8):3044–3050. doi:10.1210/jc.2008-2216

    Article  CAS  Google Scholar 

  6. Gougeon R, Marliss EB, Jones PJ, Pencharz PB, Morais JA (1998) Effect of exogenous insulin on protein metabolism with differing nonprotein energy intakes in Type 2 diabetes mellitus. Int J Obes Relat Metab Disord 22(3):250–261

    Article  CAS  Google Scholar 

  7. Pereira S, Marliss EB, Morais JA, Chevalier S, Gougeon R (2008) Insulin resistance of protein metabolism in type 2 diabetes. Diabetes 57(1):56–63. doi:10.2337/db07-0887

    Article  CAS  Google Scholar 

  8. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9(4):311–326

    Article  CAS  Google Scholar 

  9. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, Ilkayeva OR, Wenner BR, Bain JR, Lee JJ, Lim SC, Khoo CM, Shah SH, Newgard CB (2010) Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 53(4):757–767

  10. Holloszy JO (2005) Exercise-induced increase in muscle insulin sensitivity. J Appl Physiol 99(1):338–343

    Article  CAS  Google Scholar 

  11. Marliss EB, Vranic M (2002) Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes. Diabetes 51(Suppl 1):S271–S283

    Article  CAS  Google Scholar 

  12. Zinman B, Ruderman N, Campaigne BN, Devlin JT, Schneider SH (2004) Physical activity/exercise and diabetes. Diabetes Care 27(Suppl 1):S58–S62

    Google Scholar 

  13. Diabetes Prevention Program (DPP) Research Group (2002) The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 25(12):2165–2171

    Article  Google Scholar 

  14. Delahanty LM, Nathan DM (2008) Implications of the diabetes prevention program and Look AHEAD clinical trials for lifestyle interventions. J Am Diet Assoc 108(4 Suppl 1):S66–S72. doi:10.1016/j.jada.2008.01.026

    Article  Google Scholar 

  15. Peterson RG, Shaw WN, Neel M-A, Little LA, Eichberg J (1990) Zucker diabetic fatty rat as a model for non-insulin-dependent diabetes mellitus. ILAR 32(3):16–19

    Article  Google Scholar 

  16. Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, Buckingham RE (2001) Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 50(5):1021–1029

    Article  CAS  Google Scholar 

  17. Kiraly MA, Bates HE, Kaniuk NA, Yue JT, Brumell JH, Matthews SG, Riddell MC, Vranic M (2008) Swim training prevents hyperglycemia in ZDF rats: mechanisms involved in the partial maintenance of beta-cell function. Am J Physiol Endocrinol Metab 294(2):E271–E283

    Article  CAS  Google Scholar 

  18. Kiraly MA, Bates HE, Yue JT, Goche-Montes D, Fediuc S, Park E, Matthews SG, Vranic M, Riddell MC (2007) Attenuation of type 2 diabetes mellitus in the male Zucker diabetic fatty rat: the effects of stress and non-volitional exercise. Metabolism 56(6):732–744

    Article  CAS  Google Scholar 

  19. Dunn MA, Hartsook EW (1980) Comparative amino acid and protein metabolism in obese and non-obese Zucker rats. J Nutr 110(9):1865–1879

    CAS  Google Scholar 

  20. She P, Olson KC, Kadota Y, Inukai A, Shimomura Y, Hoppel CL, Adams SH, Kawamata Y, Matsumoto H, Sakai R, Lang CH, Lynch CJ (2013) Leucine and protein metabolism in obese Zucker rats. PLoS One 8(3):e59443. doi:10.1371/journal.pone.0059443

    Article  CAS  Google Scholar 

  21. Glass DJ (2005) Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 37(10):1974–1984

    Article  CAS  Google Scholar 

  22. Kimball SR, Shantz LM, Horetsky RL, Jefferson LS (1999) Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J Biol Chem 274(17):11647–11652

    Article  CAS  Google Scholar 

  23. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484. doi:10.1016/j.cell.2006.01.016

    Article  CAS  Google Scholar 

  24. Mammucari C, Schiaffino S, Sandri M (2008) Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy 4(4):524–526

    Article  CAS  Google Scholar 

  25. Adams SH (2011) Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state. Adv Nutr Int Rev J 2(6):445–456. doi:10.3945/an.111.000737

    Article  CAS  Google Scholar 

  26. Caballero B, Wurtman RJ (1991) Differential effects of insulin resistance on leucine and glucose kinetics in obesity. Metabolism 40(1):51–58

    Article  CAS  Google Scholar 

  27. Felig P, Marliss E, Cahill GF Jr (1969) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281(15):811–816

    Article  CAS  Google Scholar 

  28. Adegoke OA, Chevalier S, Morais JA, Gougeon R, Kimball SR, Jefferson LS, Wing SS, Marliss EB (2009) Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men. Am J Physiol Endocrinol Metab 296(1):E105–E113

    Article  CAS  Google Scholar 

  29. Bassil M, Burgos S, Marliss EB, Morais JA, Chevalier S, Gougeon R (2011) Hyperaminoacidaemia at postprandial levels does not modulate glucose metabolism in type 2 diabetes mellitus. Diabetologia 54(7):1810–1818. doi:10.1007/s00125-011-2115-7

    Article  CAS  Google Scholar 

  30. Wijekoon EP, Skinner C, Brosnan ME, Brosnan JT (2004) Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. Can J Physiol Pharmacol 82(7):506–514. doi:10.1139/y04-067y04-067

    Article  CAS  Google Scholar 

  31. Abumrad NN, Robinson RP, Gooch BR, Lacy WW (1982) The effect of leucine infusion on substrate flux across the human forearm. J Surg Res 32(5):453–463

    Article  CAS  Google Scholar 

  32. Tessari P, Inchiostro S, Biolo G, Duner E, Nosadini R, Tiengo A, Crepaldi G (1985) Hyperaminoacidaemia reduces insulin-mediated glucose disposal in healthy man. Diabetologia 28(11):870–872

    Article  CAS  Google Scholar 

  33. Fiehn O, Garvey WT, Newman JW, Lok KH, Hoppel CL, Adams SH (2010) Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS One 5(12):e15234. doi:10.1371/journal.pone.0015234

    Article  Google Scholar 

  34. Laferrere B, Reilly D, Arias S, Swerdlow N, Gorroochurn P, Bawa B, Bose M, Teixeira J, Stevens RD, Wenner BR, Bain JR, Muehlbauer MJ, Haqq A, Lien L, Shah SH, Svetkey LP, Newgard CB (2011) Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med 3(80):80re82. doi:10.1126/scitranslmed.3002043

    Google Scholar 

  35. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys SM, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin RH, Bettaieb A, Haj FG, Permana PA, Anthony TG, Adams SH (2013) Regulation of adipose branched chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. doi:10.1152/ajpendo.00630.2012

    Google Scholar 

  36. Campbell JE, Kiraly MA, Atkinson DJ, D’Souza AM, Vranic M, Riddell MC (2010) Regular exercise prevents the development of hyperglucocorticoidemia via adaptations in the brain and adrenal glands in male Zucker diabetic fatty rats. Am J Physiol Regul Integr Comp Physiol 299(1):R168–R176. doi:10.1152/ajpregu.00155.2010

    Article  CAS  Google Scholar 

  37. Kiraly MA, Campbell J, Park E, Bates HE, Yue JT, Rao V, Matthews SG, Bikopoulos G, Rozakis-Adcock M, Giacca A, Vranic M, Riddell MC (2010) Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. Am J Physiol Endocrinol Metab 298(3):E671–E682. doi:10.1152/ajpendo.90575.2008

    Article  CAS  Google Scholar 

  38. Phillips SM (2010) Out-FOX(O)ing proteolysis in sepsis. J physiol 588(Pt 8):1193. doi:10.1113/jphysiol.2010.189498

    Article  CAS  Google Scholar 

  39. Tremblay F, Lavigne C, Jacques H, Marette A (2007) Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 27:293–310

    Article  CAS  Google Scholar 

  40. Holecek M, Kovarik M (2011) Alterations in protein metabolism and amino acid concentrations in rats fed by a high-protein (casein-enriched) diet—effect of starvation. Food Chem Toxicol 49(12):3336–3342. doi:10.1016/j.fct.2011.09.016

    Article  CAS  Google Scholar 

  41. Herrero MC, Remesar X, Blade C, Arola L (1997) Muscle amino acid pattern in obese rats. Int J Obes Relat Metab Disord 21(8):698–703

    Article  CAS  Google Scholar 

  42. Christophe J, Winand J, Kutzner R, Hebbelinck M (1971) Amino acid levels in plasma, liver, muscle, and kidney during and after exercise in fasted and fed rats. Am J Physiol 221(2):453–457

    CAS  Google Scholar 

  43. Essen-Gustavsson B, Blomstrand E (2002) Effect of exercise on concentrations of free amino acids in pools of type I and type II fibres in human muscle with reduced glycogen stores. Acta Physiol Scand 174(3):275–281

    Article  CAS  Google Scholar 

  44. Kobayashi R, Shimomura Y, Murakami T, Nakai N, Otsuka M, Arakawa N, Shimizu K, Harris RA (1999) Hepatic branched-chain alpha-keto acid dehydrogenase complex in female rats: activation by exercise and starvation. J Nutr Sci Vitaminol (Tokyo) 45(3):303–309

    Article  CAS  Google Scholar 

  45. Xu M, Nagasaki M, Obayashi M, Sato Y, Tamura T, Shimomura Y (2001) Mechanism of activation of branched-chain alpha-keto acid dehydrogenase complex by exercise. Biochem Biophys Res Commun 287(3):752–756

    Article  CAS  Google Scholar 

  46. Thong FS, Derave W, Kiens B, Graham TE, Urso B, Wojtaszewski JF, Hansen BF, Richter EA (2002) Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise. Diabetes 51(3):583–590

    Article  CAS  Google Scholar 

  47. Wojtaszewski JF, Hansen BF, Kiens B, Gade, Markuns JF, Goodyear LJ, Richter EA (2000) Insulin signaling and insulin sensitivity after exercise in human skeletal muscle. Diabetes 49(3):325–331

    Article  CAS  Google Scholar 

  48. Op den Kamp CM, Langen RC, Snepvangers FJ, de Theije CC, Schellekens JM, Laugs F, Dingemans AM, Schols AM (2013) Nuclear transcription factor kappaB activation and protein turnover adaptations in skeletal muscle of patients with progressive stages of lung cancer cachexia. Am J Clin Nutr. doi:10.3945/ajcn.113.058388

    Google Scholar 

  49. Liu HY, Hong T, Wen GB, Han J, Zuo D, Liu Z, Cao W (2009) Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance. Am J Physiol Endocrinol Metab 297(4):E898–E906. doi:10.1152/ajpendo.00374.2009

    Article  CAS  Google Scholar 

  50. Tato I, Bartrons R, Ventura F, Rosa JL (2011) Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J Biol Chem 286(8):6128–6142. doi:10.1074/jbc.M110.166991

    Article  CAS  Google Scholar 

  51. Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Mendez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL (2013) Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids. J Biol Chem 288(15):10640–10651. doi:10.1074/jbc.M113.455998

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. L.S. Jefferson and S.R. Kimball for their generous guidance, and Donato Brunetti, Marie Lamarche and Ginette Sabourin for technical assistance. This work was supported by Canadian Institute for Health Research (CIHR) grant to E.B. Marliss (MOP-62889), and to M. Vranic and M. C. Riddell (MOP-2197). H. E. Bates was supported by a CIHR Canada Graduate Scholarship Doctoral Award. M. A. Kiraly was a recipient of Natural Science and Engineering Research Council of Canada (NSERC) Doctoral Award and Banting and Best Diabetes Centre (BBDC) Novo Nordisk Scholarship.

Conflict of interest

The authors declare there is no conflict of interest in relation to this work.

Author information

Author notes

  1. Holly E. Bates

    Present address: Trent University, Peterborough, ON, Canada

  2. Michael A. Kiraly

    Present address: Department of Biology, Capilano University, North Vancouver, BC, Canada

Authors and Affiliations

  1. Crabtree Nutrition Laboratories, Division of Endocrinology and Metabolism, Department of Medicine, McGill University Health Centre, Montreal, Canada

    Olasunkanmi A. J. Adegoke & Errol B. Marliss

  2. School of Kinesiology and Health Science, York University, Toronto, ON, M3J 1P3, Canada

    Olasunkanmi A. J. Adegoke & Michael C. Riddell

  3. Departments of Physiology and Medicine, University of Toronto, Toronto, Canada

    Holly E. Bates, Michael A. Kiraly & Mladen Vranic

Authors
  1. Olasunkanmi A. J. Adegoke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Holly E. Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. Kiraly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mladen Vranic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael C. Riddell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Errol B. Marliss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Olasunkanmi A. J. Adegoke.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adegoke, O.A.J., Bates, H.E., Kiraly, M.A. et al. Exercise in ZDF rats does not attenuate weight gain, but prevents hyperglycemia concurrent with modulation of amino acid metabolism and AKT/mTOR activation in skeletal muscle. Eur J Nutr 54, 751–759 (2015). https://doi.org/10.1007/s00394-014-0754-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-014-0754-4

Keywords

Search

Navigation