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Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis

International Journal of Obesity volume 31, pages 1596–1604 (2007)Cite this article

Abstract

Objective:

To investigate whether changes in body energy balance induced by long-term high-fat feeding in adult rats could be associated with modifications in energetic behaviour and oxidative stress of skeletal muscle subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations.

Design:

Adult rats were fed low-fat or high-fat diet for 7 weeks.

Measurements:

Body energy balance and composition analysis together with plasma insulin and glucose level determination in the whole animal. Oxidative capacity, basal and induced proton leaks as well as aconitase and superoxide dismutase activities in SS and IMF mitochondria from skeletal muscle.

Results:

High-fat fed rats exhibit increased body lipid content, as well as hyperinsulinemia, hyperglycaemia and higher plasma non-esterified fatty acids. In addition, SS mitochondria display lower respiratory capacity and a different behaviour of SS and IMF mitochondria is found in the prevention from oxidative damage.

Conclusions:

A deleterious consequence of decreased oxidative capacity in SS mitochondria from rats fed high-fat diet would be a reduced utilization of energy substrates, especially fatty acids, which may lead to intracellular triglyceride accumulation, lipotoxicity and insulin resistance development. Our results thus reveal a possible role for SS mitochondria in the impairment of glucose homeostasis induced by high-fat diet.

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References

  1. Han D, Hansen PA, Host HH, Holloszy JO . Insulin resistance of muscle glucose transport in rats fed a high fat diet. Diabetes 1997; 46: 1761–1767.

    Article  CAS  Google Scholar 

  2. Bernstein RS, Marshall MC, Caney AL . Effects of dietary composition on adipose tissue hexokinase-2 and glucose utilization in normal and streptozotocin-diabetic rats. Diabetes 1977; 26: 770–779.

    Article  CAS  Google Scholar 

  3. Kraegen EW, Clark PW, Jenkins AB, Daley E, Chisholm DJ, Storlien LH . Development of muscle insulin resistance after liver insulin resistance in the high fat fed rat. Diabetes 1991; 40: 1397–1403.

    Article  CAS  Google Scholar 

  4. Kelley DE, Mintun MA, Watkins SC, Simoneau JA, Jadili F, Fredrickson A et al. The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J Clin Invest 1996; 97: 2705–2713.

    Article  CAS  Google Scholar 

  5. Furler SM, Oakes ND, Watkinson AL, Kraegen EW . A high-fat diet influences insulin-stimulated posttransport muscle glucose metabolism in rat. Metabolism 1997; 46: 1101–1106.

    Article  CAS  Google Scholar 

  6. Ikemoto S, Thompson KS, Takahashi M, Itakura H, Lane MD, Ezaki O . High fat diet induced hyperglicemia. prevention by low level expression of a glucose transporter (GLUT4) minigene in transgenic mouse. Proc Natl Acad Sci USA 1995; 92: 3096–3099.

    Article  CAS  Google Scholar 

  7. Zhou YP, Grill VE . Long term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 1994; 93: 870–876.

    Article  CAS  Google Scholar 

  8. Sako Y, Grill VE . A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 1990; 127: 1580–1589.

    Article  CAS  Google Scholar 

  9. Carpentier A, Mittelman SD, Lamarche B, Bergman RN, Giacca A, Lewis GF . Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am J Physiol Endocrinol Metab 1999; 276: E1055–E1066.

    Article  CAS  Google Scholar 

  10. Paolisso G, Gambardella A, Amato L, Tortoriello R, D'Amore A, Varricchio M et al. Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia 1995; 38: 1295–1299.

    Article  CAS  Google Scholar 

  11. Oakes ND, Bell KS, Furler SM, Camilleri S, Saha AK, Ruderman NB et al. Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl CoA. Diabetes 1997; 46: 2022–2028.

    Article  CAS  Google Scholar 

  12. Chalkley SM, Hettiarachchi M, Chisholm DJ, Kraegen EW . Long-term high fat feeding leads to severe insulin resistance but not diabetes in Wistar rats. Am J Physiol Endocrinol Metab 2002; 282: E1231–E1238.

    Article  CAS  Google Scholar 

  13. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW . Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991; 40: 280–289.

    Article  CAS  Google Scholar 

  14. Stark AH, Timar B, Madar Z . Adaptation of Sprague Dawley rats to long-term feeding of high fat or high fructose diets. Eur J Nutr 2000; 39: 229–234.

    Article  CAS  Google Scholar 

  15. Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE . Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54: 8–14.

    Article  CAS  Google Scholar 

  16. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI . Impaired mitochondrial activity in the insulin-resistant qoffspring of patients with type 2 diabetes. N Engl J Med 2004; 350: 664–671.

    Article  CAS  Google Scholar 

  17. Stannard SR, Johnson NA . Insulin resistance and elevated triglyceride in muscle: more important for survival than thrifty genes? J Physiol 2003; 554: 595–607.

    Article  Google Scholar 

  18. Iossa S, Lionetti L, Mollica MP, Crescenzo R, Botta M, Barletta A et al. Effect of high fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats. Br J Nutr 2003; 90: 953–960.

    Article  CAS  Google Scholar 

  19. Mollica MP, Lionetti L, Crescenzo R, D'Andrea E, Ferraro M, Liverini G et al. Heterogeneous bioenergetic behaviour of subsarcolemmal and intermyofibrillar mitochondria in fed and fasted rats. Cell Mol Life Sci 2005; 63: 358–366.

    Article  Google Scholar 

  20. Sreekumar R, Unnikrishnan J, Fu A, Nygren J, Short KR, Shimke J et al. Impact of high-fat diet and antioxidant supplement on mitochondrial funcions and gene transcripts in rat muscle. Am J Physiol Endocrinol Metab 2002; 282: E1055–E1061.

    Article  CAS  Google Scholar 

  21. Slim RM, Toborek M, Watkins BA, Boissonneault GA, Hennig B . Susceptibility to hepatic oxidative stress in rabbits fed different animal and plant fats. J Am Coll Nutr 1996; 15: 289–294.

    Article  CAS  Google Scholar 

  22. Iossa S, Mollica MP, Lionetti L, Crescenzo R, Botta M, Liverini G . Skeletal muscle oxidative capacity in rats fed high-fat diet. Int J Obes 2002; 26: 65–72.

    Article  CAS  Google Scholar 

  23. Folch J, Lees M, Stanley GHS . A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–510.

    CAS  Google Scholar 

  24. Iossa S, Lionetti L, Mollica MP, Barletta A, Liverini G . Energy intake and utilization vary during development in rats. J Nutr 1999; 129: 1593–1596.

    Article  CAS  Google Scholar 

  25. Pullar JD, Webster AJF . The energy cost of fat and protein deposition in the rat. Br J Nutr 1977; 37: 355–363.

    Article  CAS  Google Scholar 

  26. Rothwell NJ, Stock MJ, Warwick BP . Energy balance and brown fat activity in rats fed cafeteria diets or high fat, semisynthetic diets at several levels of intake. Metab 1985; 34: 474–480.

    Article  CAS  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  28. Iossa S, Mollica MP, Lionetti L, Crescenzo R, Botta M, Samec S et al. Skeletal muscle mitochondrial efficiency and uncoupling protein 3 in overeating rats with increased thermogenesis. Pflug Arch 2002; 445: 431–436.

    Article  Google Scholar 

  29. Srere PA . Citrate synthase. Methods Enzymol 1969; 13: 3–5.

    Article  CAS  Google Scholar 

  30. Estabrook RW . Mitochondrial respiratory control and the polarographic measurement of ADP:O ratios. Methods Enzymol 1967; 10: 41–47.

    Article  CAS  Google Scholar 

  31. Nedergaard J . The relationship between extramitochondrial Ca2+ concentration, respiratory rate, and membrane potential in mitochondria from brown adipose tissue of the rat. Eur J Biochem 1983; 133: 185–191.

    Article  CAS  Google Scholar 

  32. Iossa S, Mollica MP, Lionetti L, Crescenzo R, Tasso R, Liverini G . A possible link between skeletal muscle mitochondrial efficiency and age-induced insulin resistance. Diabetes 2004; 53: 2861–2866.

    Article  CAS  Google Scholar 

  33. Richieri GV, Anel A, Kleinfeld AM . Interactions of long chain fatty acids and albumin: determination of free fatty acid levels using the fluorescent probe ADIFAB. Biochemistry 1993; 32: 7574–7580.

    Article  CAS  Google Scholar 

  34. Gardner PR . Aconitase: sensitive target and measure of superoxide. Methods Enzymol 2002; 349: 9–16.

    Article  CAS  Google Scholar 

  35. Hausladen A, Fridovich I . Measuring nitric oxide and superoxide: rate constants for aconitase reactivity. Methods Enzymol 1996; 269: 37–41.

    Article  CAS  Google Scholar 

  36. Flohè L, Otting F . Superoxide Dismutase Assay. Methods Enzymol 1984; 105: 93–104.

    Article  Google Scholar 

  37. Krieger DA, Tate CA, McMillin-Wood J, Booth FW . Populations of rat skeletal muscle mitocondria after exercise and immobilization. J Appl Physiol 1980; 48: 23–28.

    Article  CAS  Google Scholar 

  38. Cogswell AM, Stevens RJ, Hood DA . Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Am J Physiol 1993; 264: C383–C389.

    Article  CAS  Google Scholar 

  39. Bizeau ME, Willis WT, Hazel JR . Differential responses to endurance training in subsarcolemmal and intermyofibrillar mitochondria. J Appl Physiol 1998; 85: 1279–1284.

    Article  CAS  Google Scholar 

  40. Rolfe DSF, Brown CG . Cellular energy utilisation and molecular origin of standard metabolic rate in mammals. Physiol Rev 1997; 77: 731–758.

    Article  CAS  Google Scholar 

  41. Skulachev VP . Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 1991; 294: 158–162.

    Article  CAS  Google Scholar 

  42. Jezek P, Engstova H, Zackova M, Vercesi AE, Costa ADT, Arruta P et al. Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Biochim Biophys Acta 1998; 1365: 319–327.

    Article  CAS  Google Scholar 

  43. Boozer CN, Schoenbach B, Atkinson RL . Dietary fat and adiposity: a dose-response relationship in adult male rats fed isocalorically. Am J Physiol 1995; 268: E546–E550.

    CAS  PubMed  Google Scholar 

  44. Boozer CN, Brasseur A, Atkinson RL . Dietary fat affects weight loss and adiposity during energy restriction in rats. Am J Clin Nutr 1993; 58: 846–852.

    Article  CAS  Google Scholar 

  45. Flatt JP . The biochemistry of energy expenditure. In: Bjorntorp P and Bordoff BN (eds). Obesity. Lippincott: Philadelphia, PA, 1992; 110–116.

    Google Scholar 

  46. Jequier E . Pathways to obesity. Int J Obes 2002; 26: S12–S17.

    Article  CAS  Google Scholar 

  47. Kaloyianni M, Freedland RA . Contribution of several aminoacids and lactate to gluconeogenesis in hepatocytes isolated from rats fed various diets. J Nutr 1990; 120: 116–122.

    Article  CAS  Google Scholar 

  48. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA et al. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005; 54: 1926–1933.

    Article  CAS  Google Scholar 

  49. Jagoe RT, Lecker SH, Gomes M, Goldberg AL . Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. FASEB J 2002; 16: 1697–1712.

    Article  CAS  Google Scholar 

  50. Robblee NM, Clandinin MT . Effect of dietary fat level and polyunsaturated fatty acid content on the phospholipid composition of rat cardiac mitochondrial membranes and mitochondrial ATPase activity. J Nutr 1984; 114: 263–269.

    Article  CAS  Google Scholar 

  51. Ramsey J, Harper ME, Humble SJ, Koomson EK, Ram JJ, Bevilacqua L et al. Influence of mitochondrial membrane fatty acid composition on proton leak and H2O2 production in liver. Comp Biochem Physiol 2005; 140: 99–108.

    Article  Google Scholar 

  52. Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC et al. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003; 362: 951–957.

    Article  CAS  Google Scholar 

  53. Petersen KF, Befroy D, Dofour S, Dziura J, Arijan C, Rothman DL et al. Mitochondrial disfunction in the elderly: possible role in insulin resistance. Science 2003; 300: 1140–1142.

    Article  CAS  Google Scholar 

  54. Bruce CR, Anderson MJ, Carey AL, Newman DG, Bonen A, Kriketos AD et al. Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status. J Clin Endocrinol Metab 2003; 88: 5444–5451.

    Article  CAS  Google Scholar 

  55. Pamploma R, Portero-Otin M, Sanz A, Requena J, Barja G . Modification of the longevity-related degree of fatty acid unsaturation modulates oxidative damage to proteins and mitochondrial DNA in liver and brain. Exp Gerontol 2004; 39: 725–733.

    Article  Google Scholar 

  56. Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G . Effect of the degree of fatty acid unsaturation of rat heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage. Mech Ageing Dev 2001; 122: 427–443.

    Article  CAS  Google Scholar 

  57. Korshunov SS, Skulachev VP, Starkov AA . High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 1997; 416: 15–18.

    Article  CAS  Google Scholar 

  58. Crescenzo R, Lionetti L, Mollica MP, Ferraro M, D'Andrea E, Mainieri D et al. Altered skeletal muscle subsarcolemmal mitochondrial compartment during catch-up fat after caloric restriction. Diabetes 2006; 55: 2286–2293.

    Article  CAS  Google Scholar 

  59. Kerner J, Turkaly PJ, Minkler PE, Hoppel CL . Aging skeletal muscle mitochondria in the rat: decreased uncoupling protein-3 content. Am J Physiol 2001; 281: E1054–E1062.

    CAS  Google Scholar 

  60. Hoeks J, Hesselink MKC, Schrauwen P . Involvement of UCP3 in mild uncoupling and lipotoxicity. Exp Gerontol 2006; 41: 658–662.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant MIUR-COFIN 2004. We thank Dr Emilia De Santis for her skilful management of animal house.

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Authors and Affiliations

  1. Department of Biological Sciences, Section of Physiology, University of Naples ‘FEDERICO II’, Naples, Italy

    L Lionetti, M P Mollica, R Crescenzo, E D'Andrea, M Ferraro, F Bianco, G Liverini & S Iossa

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  1. L Lionetti
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  2. M P Mollica
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Correspondence to S Iossa.

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Lionetti, L., Mollica, M., Crescenzo, R. et al. Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int J Obes 31, 1596–1604 (2007). https://doi.org/10.1038/sj.ijo.0803636

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