Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat

International Journal of Obesity volume 26, pages 308–317 (2002)Cite this article

Abstract

OBJECTIVE: To characterize the developmental changes in adipose and muscle lipoprotein lipase (LPL) activity in the atherosclerosis-prone JCR:LA-corpulent rat, and to test the hypothesis that tissue-specific abnormalities in LPL activity precede the establishment of obesity.

DESIGN: Lean (+/?) and obese cp/cp male JCR:LA rats were studied at 4, 5 and 8 weeks of age, that is at the onset of obesity, and at a time when obesity is well established. Assessment was made of plasma variables related to glucose and lipid metabolism and of LPL activity in several adipose depots, skeletal muscles and the heart.

RESULTS: At week 4, body weights were identical in both genotypes and began to diverge at week 5. Eight-week-old cp/cp rats weighed 35% more than their lean counterparts. Perirenal and epididymal adipose depot weights were also identical in both genotypes at week 4 and began to increase in cp/cp rats at week 5, whereas the subcutaneous depot of 4-week-old cp/cp rats was slightly enlarged. At week 4, the cp/cp rats were hyperinsulinemic (5-fold), hyperleptinemic (30-fold) and hypertriglyceridemic (3-fold) compared to their lean counterparts, and their liver contained twice as much triglyceride. The 4-week-old cp/cp rats displayed 2–7-fold higher LPL specific activity in the various adipose depots compared to lean rats, and enzyme activity remained higher in obese than in lean rats at all subsequent ages. In contrast, LPL activity in the vastus lateralis, gastrocnemius and heart muscles of 4-week-old obese rats was approximately half that observed in lean animals.

CONCLUSION: Profound, persistent alterations in the tissue-specific modulation of LPL activity are established in the JCR:LA cp/cp rat prior to the development of frank obesity. The increase in adipose tissue LPL activity and its decrease in muscle tissues are likely to be related to the concomitant alterations in insulinemia and triglyceridemia, respectively. The pre-obesity, tissue-specific alterations in LPL activity may be considered as an integrated adaptation to increased lipid flux aimed at driving lipids toward storage sites and limiting their uptake by triglyceride-laden muscles.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Reaven GM . Banting lecture 1988. Role of insulin resistance in human disease Diabetes 1988 37: 1595–1607.

    Article  CAS  PubMed  Google Scholar 

  2. Howard BV . Lipoprotein metabolism in diabetes Curr Opin Lipidol 1994 5: 216–220.

    Article  CAS  PubMed  Google Scholar 

  3. Després J-P . Dyslipidaemia and obesity Baillière Clin Endocrinol Metab 1994 8: 629–660.

    Article  Google Scholar 

  4. Eckel RH . Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases New Engl J Med 1989 320: 1060–1068.

    Article  CAS  PubMed  Google Scholar 

  5. Boulange A, Planche E, de Gasquet P . Onset and development of hypertriglyceridemia in the Zucker rat (fa/fa) Metabolism 1981 30: 1045–1052.

    Article  CAS  PubMed  Google Scholar 

  6. Gruen R, Hietanen E, Greenwood MR . Increased adipose tissue lipoprotein lipase activity during the development of the genetically obese rat (fa/fa) Metabolism 1978 27: 1955–1966.

    Article  CAS  PubMed  Google Scholar 

  7. Auwerx J . PPARγ, the ultimate thrifty gene Diabetologia 1999 42: 1033–1049.

    Article  CAS  PubMed  Google Scholar 

  8. Cleary MP, Vasselli JR, Greenwood MR . Development of obesity in Zucker obese (fa/fa) rat in absence of hyperphagia Am J Physiol Endocrinol Metab 1980 238: E284–E292.

    Article  CAS  Google Scholar 

  9. Boivin A, Deshaies Y . Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat Metabolism 2000 49: 134–140.

    Article  CAS  PubMed  Google Scholar 

  10. Picard F, Richard D, Timofeeva E, Deshaies Y . Abnormal insulin and β-adrenergic modulation of lipoprotein lipase during refeeding after prolonged fasting in the Zucker rat Diabetologia 2000 43: 866–874.

    Article  CAS  PubMed  Google Scholar 

  11. MacDougald OA, Hwang CS, Fan H, Lane MD . Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes Proc Natl Acad Sci USA 1995 92: 9034–9037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach G . Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans Endocrinology 1998 139: 822–826.

    Article  CAS  PubMed  Google Scholar 

  13. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF . Leptin suppression of insulin secretion by the activation of ATP- sensitive K+ channels in pancreatic beta-cells Diabetes 1997 46: 1087–1093.

    Article  CAS  PubMed  Google Scholar 

  14. Trayhurn P . New insights into the development of obesity: obese genes and the leptin system Proc Nutr Soc 1996 55: 783–791.

    Article  CAS  PubMed  Google Scholar 

  15. Amy RM, Dolphin PJ, Pederson RA, Russell JC . Atherogenesis in two strains of obese rats. The fatty Zucker and LA/N- corpulent Atherosclerosis 1988 69: 199–209.

    Article  CAS  PubMed  Google Scholar 

  16. Rainwater DL, Comuzzie AG, VandeBerg JL, Mahaney MC, Blangero J . Serum leptin levels are independently correlated with two measures of HDL Atherosclerosis 1997 132: 237–243.

    Article  CAS  PubMed  Google Scholar 

  17. Koletsky S . Pathologic findings and laboratory data in a new strain of obese hypertensive rats Am J Pathol 1975 80: 129–142.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu-Peng XS, Chua SC Jr, Okada N, Liu SM, Nicolson M, Leibel RL . Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat Diabetes 1997 46: 513–518.

    Article  CAS  PubMed  Google Scholar 

  19. Russell JC, Shillabeer G, Bar-Tana J, Lau DC, Richardson M, Wenzel LM, Graham SE, Dolphin PJ . Development of insulin resistance in the JCR:LA-cp rat: role of triacylglycerols and effects of MEDICA 16 Diabetes 1998 47: 770–778.

    Article  CAS  PubMed  Google Scholar 

  20. Russell JC, Graham SE, Dolphin PJ . Glucose tolerance and insulin resistance in the JCR:LA-corpulent rat: effect of miglitol (Bay m 1099) Metabolism 1999 48: 701–706.

    Article  CAS  PubMed  Google Scholar 

  21. Russell JC . The atherosclerosis-prone JCR:LA-corpulent rat. In: Woodford FP, Davignon J, Sniderman A (eds). Atherosclerosis X: Proceedings of the 10th International Symposium on Atherosclerosis. Elsevier: Amsterdam 1995 121–125.

    Google Scholar 

  22. Russell JC, Graham SE, Richardson M . Cardiovascular disease in the JCR:LA-cp rat Mol Cell Biochem 1998 188: 113–126.

    Article  CAS  PubMed  Google Scholar 

  23. Russell JC, Amy RM, Graham SE, Dolphin PJ, Wood GO, Bar-Tana J . Inhibition of atherosclerosis and myocardial lesions in the JCR:LA-cp rat by β, β′-tetramethylhexadecanedioic acid (MEDICA 16) Arterioscler Thromb Vasc Biol 1995 15: 918–923.

    Article  CAS  PubMed  Google Scholar 

  24. Russell JC, Koeslag DG, Amy RM, Dolphin PJ . Independence of myocardial disease in the JCR:LA-corpulent rat on plasma chol-esterol concentration Clin Invest Med 1991 14: 288–295.

    CAS  PubMed  Google Scholar 

  25. Folch J, Lees M, Sloane Stanley GH . A simple method for the isolation and purification of total lipids from animal tissues J Biol Chem 1957 226: 497–509.

    CAS  PubMed  Google Scholar 

  26. Paulin A, Lalonde J, Deshaies Y . β-Adrenergic blockade and lipoprotein lipase activity in rat tissues after acute exercise Am J Physiol Regulat Integrative Comp Physiol 1991 261: R891–R897.

    Article  CAS  Google Scholar 

  27. Belfrage P, Vaughan M . Simple liquid–liquid partition system for isolation of labeled oleic acid from mixtures with glycerides J Lipid Res 1969 10: 341–344.

    CAS  PubMed  Google Scholar 

  28. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ . Protein measurement with the Folin phenol reagent J Biol Chem 1951 193: 265–275.

    CAS  PubMed  Google Scholar 

  29. Chan CB, Pederson RA, Buchan AM, Tubesing KB, Brown JC . Gastric inhibitory polypeptide and hyperinsulinemia in the Zucker (fa/fa) rat: a developmental study Int J Obes Relat Metab Disord 1985 9: 137–146.

    CAS  Google Scholar 

  30. Russell JC, Koeslag DG, Amy RM, Dolphin PJ . Plasma lipid secretion and clearance in hyperlipidemic JCR:LA-corpulent rats Arteriosclerosis 1989 9: 869–876.

    Article  CAS  PubMed  Google Scholar 

  31. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G . Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans J Clin Invest 1995 95: 158–166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kazumi T, Hirano T, Odaka H, Ebara T, Amano N, Hozumi T, Ishida Y, Yoshino G . VLDL triglyceride kinetics in Wistar fatty rats, an animal model of NIDDM: effects of dietary fructose alone or in combination with pioglitazone Diabetes 1996 45: 806–811.

    Article  CAS  PubMed  Google Scholar 

  33. Chua SC, White DW, Wupeng XS, Liu SM, Okada N, Kershaw EE, Chung WK, Powerkehoe L, Chua M, Tartaglia LA, Leibel RL . Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr) Diabetes 1996 45: 1141–1143.

    Article  CAS  PubMed  Google Scholar 

  34. Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M . Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion Diabetes 1997 46: 313–316.

    Article  CAS  PubMed  Google Scholar 

  35. Russell JC, Graham S, Hameed M . Abnormal insulin and glucose metabolism in the JCR:LA-corpulent rat Metabolism 1994 43: 538–543.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue Nature 1994 372: 425–432.

    Article  CAS  PubMed  Google Scholar 

  37. Pagano C, Englaro P, Granzotto M, Blum WF, Sagrillo E, Ferretti E, Federspil G, Vettor R . Insulin induces rapid changes of plasma leptin in lean but not in genetically obese (fa/fa) rats Int J Obes Relat Metab Disord 1997 21: 614–618.

    Article  CAS  PubMed  Google Scholar 

  38. Rayner DV, Dalgliesh GD, Duncan JS, Hardie LJ, Hoggard N, Trayhurn P . Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats Am J Physiol Regulat Integrative Comp Physiol 1997 273: R446–450.

    Article  CAS  Google Scholar 

  39. Shillabeer G, Vydelingum S, Hatch G, Russell JC, Lau DC . Long-term regulation of leptin expression is correlated with adipocyte number in obese rats Clin Invest Med 1998 21: 54–62.

    CAS  PubMed  Google Scholar 

  40. Barr VA, Malide D, Zarnowski MJ, Taylor SI, Cushman SW . Insulin stimulates both leptin secretion and production by rat white adipose tissue Endocrinology 1997 138: 4463–4472.

    Article  CAS  PubMed  Google Scholar 

  41. Bradley RL, Cheatham B . Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes Diabetes 1999 48: 272–278.

    Article  CAS  PubMed  Google Scholar 

  42. Russell CD, Petersen RN, Rao SP, Ricci MR, Prasad A, Zhang Y, Brolin RE, Fried SK . Leptin expression in adipose tissue from obese humans: depot-specific regulation by insulin and dexamethasone Am J Physiol Endocrinol Metab 1998 275: E507–E515.

    Article  CAS  Google Scholar 

  43. Rayner DV, Trayhurn P . Regulation of leptin production: sympathetic nervous system interactions J Mol Med 2001 79: 8–20.

    Article  CAS  PubMed  Google Scholar 

  44. Ranganathan S, Ciaraldi TP, Henry RR, Mudaliar S, Kern PA . Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells Endocrinology 1998 139: 2509–2513.

    Article  CAS  PubMed  Google Scholar 

  45. Picard F, Naïmi N, Richard D, Deshaies Y . Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion Diabetes 1999 48: 452–459.

    Article  CAS  PubMed  Google Scholar 

  46. Eckel RH . Adipose tissue lipoprotein lipase. In: Borensztajn J (ed). Lipoprotein lipase Evener: Chicago, IL 1987 79–132.

    Google Scholar 

  47. Belahsen R, Deshaies Y . Modulation of lipoprotein lipase activity in the rat by the β2-adrenergic agonist clenbuterol Can J Physiol Pharmac 1992 70: 1555–1562.

    Article  CAS  Google Scholar 

  48. Raynolds MV, Awald PD, Gordon DF, Gutierrez-Hartmann A, Rule DC, Wood WM, Eckel RH . Lipoprotein lipase gene expression in rat adipocytes is regulated by isoproterenol and insulin through different mechanisms Mol Endocrinol 1990 4: 1416–1422.

    Article  CAS  PubMed  Google Scholar 

  49. Deshaies Y, Géloën A, Paulin A, Marette A, Bukowiecki LJ . Tissue-specific alterations in lipoprotein lipase activity in the rat after chronic infusion of isoproterenol Horm Metab Res 1993 25: 13–16.

    Article  CAS  PubMed  Google Scholar 

  50. Kiens B, Lithell H, Mikines KJ, Richter EA . Effects of insulin and exercise on muscle lipoprotein lipase activity in man and its relation to insulin action J Clin Invest 1989 84: 1124–1129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pollare T, Vessby B, Lithell H . Lipoprotein lipase activity in skeletal muscle is related to insulin sensitivity Arterioscler Thromb 1991 11: 1192–1203.

    Article  CAS  PubMed  Google Scholar 

  52. Ferraro RT, Eckel RH, Larson DE, Fontvieille AM, Rising R, Jensen DR, Ravussin E . Relationship between skeletal muscle lipoprotein lipase activity and 24-hour macronutrient oxidation J Clin Invest 1993 92: 441–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD . Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats Diabetes 2001 50: 123–130.

    Article  CAS  PubMed  Google Scholar 

  54. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI . Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study Diabetologia 1999 42: 113–116.

    Article  CAS  PubMed  Google Scholar 

  55. Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW . Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding Diabetes 1997 46: 1768–1774.

    Article  CAS  PubMed  Google Scholar 

  56. Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L . Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents Diabetes 1999 48: 1600–1606.

    Article  CAS  PubMed  Google Scholar 

  57. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI . Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance Proc Natl Acad Sci USA 2001 98: 7522–7527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are indebted to Ms Josée Lalonde and Ms Sandra E Kelly for their invaluable professional assistance. This work was supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

Author information

Authors and Affiliations

  1. Département d'anatomie et physiologie, Centre de recherche sur le métabolisme énergétique, Faculté de médecine, Université Laval, Québec, Canada

    L Mantha & Y Deshaies

  2. Department of Surgery, 275 Heritage Research Centre, University of Alberta, Edmonton, Alberta, Canada

    JC Russell

  3. Department of Biochemistry (Signal Transduction Laboratories), University of Alberta, Edmonton, Alberta, Canada

    DN Brindley

Authors
  1. L Mantha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JC Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. DN Brindley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Deshaies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Deshaies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mantha, L., Russell, J., Brindley, D. et al. Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat. Int J Obes 26, 308–317 (2002). https://doi.org/10.1038/sj.ijo.0801882

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801882

Keywords

This article is cited by

Search

Advanced search

Quick links