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Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome

Abstract

OBJECTIVE: To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub).

DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days.

MEASUREMENTS: Parameters of lipid and carbohydrate metabolism—oral glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver.

RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues.

CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoid-induced hypertriglyceridemia.

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References

  1. Haim M, Benderly M, Brunner D, Behar S, Graff E, Reicher-Reiss H, Goldbourt U . Elevated serum triglyceride levels and long-term mortality in patients with coronary heart disease: the Bezafibrate Infarction Prevention (BIP) Registry. Circulation 1999; 100: 475–482.

    Article  CAS  PubMed  Google Scholar 

  2. Cullen P . Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000; 86: 943–949.

    Article  CAS  PubMed  Google Scholar 

  3. Talmud PJ, Hawe E, Martin S, Olivier M, Miller GJ, Rubin EM, Pennacchio LA, Humphries SE . Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet 2002; 24: 3039–3046.

    Article  Google Scholar 

  4. Najib J . Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation. Clin Ther 2002; 24: 2022–2050.

    Article  CAS  PubMed  Google Scholar 

  5. Bershad S, Rubinstein A, Paterniti JR, Le NA, Poliak SC, Heller B, Ginsberg HN, Fleischmajer R, Brown WV . Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985; 313: 981–985.

    Article  CAS  PubMed  Google Scholar 

  6. Malmendier C, Lontie J, Delcroix C, Dubois D, Magot T, De Roy L . Apolipoproteins C-II and C-III metabolism in hypertryglyceridemic patients: effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration. Atherosclerosis 1989; 77: 139–149.

    Article  CAS  PubMed  Google Scholar 

  7. Vu-Dac N, Gervois P, Torra IP, Fruchart JC, Kosykh V, Kooistra T, Princen HM, Dallongeville J, Staels B . Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids. J Clin Invest 1998; 102: 625–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wojciechowski AP, Farrall M, Cullen P, Wilson TM, Bayliss JD, Farren B, Griffin BA, Caslake MJ, Packard CJ, Shepherd J, Thakker R, Scott J . Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23–q24. Nature 1991; 349: 161–164.

    Article  CAS  PubMed  Google Scholar 

  9. Kren V . Genetics of the polydactyly-luxate syndrome in the Norway rat, Rattus norvegicus. Acta Univ Carrol Med Praha (Monogr) 1975; 68: 1–103.

    Google Scholar 

  10. Kren V, Krenova D, Pravenec M, Zdobinska M . Chromosome 8 congenic strains: tools for genetic analysis of limb malformation, plasma triglycerides, and blood pressure in the rat. Folia Biol (Praha) 1995; 41: 284–293.

    CAS  Google Scholar 

  11. Kren V, Krenova D, Bila V, Zdobinska M, Zidek V, Pravenec M . Recombinant inbred and congenic strains for mapping of genes that are responsible for spontaneous hypertension and other risk factors of cardiovascular disease. Folia Biol (Praha) 1996; 42: 155–158.

    CAS  Google Scholar 

  12. Vrana A, Kazdova L, Dobesova Z, Kunes J, Kren V, Bila V, Stolba P, Klimes I . Triglyceridemia, glucoregulation, and blood pressure in various rat strains. Effects of dietary carbohydrates. Ann N Y Acad Sci 1993; 683: 57–68.

    Article  CAS  PubMed  Google Scholar 

  13. Sedova L, Kazdova L, Seda O, Krenova D, Kren V . Rat inbred PD/Cub strain as a model of dyslipidemia and insulin resistance. Folia Biol (Praha) 2000; 46: 99–106.

    CAS  Google Scholar 

  14. Seda O, Sedova L, Kazdova L, Krenova D, Kren V . Metabolic characterization of insulin resistance syndrome feature loci in three Brown Norway-derived congenic strains. Folia Biol (Praha) 2002; 48: 81–88.

    CAS  Google Scholar 

  15. Seda O, Liska F, Krenova D, Kazdova L, Sedova L, Zima T, Peng J, Tremblay J, Kren V, Hamet P . Differential linkage of triglyceride and glucose levels on rat chromosome 4 in two segregating rat populations. Folia Biol (Praha) 2003; 49: 223–226.

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Vrana A, Kazdova L . Insulin sensitivity of rat adipose tissue and of diaphragm in vitro: Effect of the type of dietary carbohydrate (starch–sucrose). Life Sci 1970; 9: 257–265.

    Article  CAS  Google Scholar 

  18. de Mazancourt P, Darimont C, Giot J, Giudicelli Y . Differential modulation of the adenylate cyclase/cyclic AMP stimulatory pathway by protein kinase C activation in rat adipose tissue and isolated fat cells. Influence of collagenase digestion. Biochem Pharmacol 1991; 42: 1791–1797.

    Article  CAS  PubMed  Google Scholar 

  19. Lönnqvist F, Arner P . Interaction between adenylate cyclase inhibitors and beta-adrenoceptors in isolated human fat cells. Biochem Biophys Res Commun 1989; 161: 654–660.

    Article  PubMed  Google Scholar 

  20. Kather H, Bieger W, Michel G, Aktories A, Jakobs KH . Human fat cell lipolysis is primarily regulated by inhibitory modulators acting through distinct mechanisms. J Clin Invest 1985; 76: 1559–1565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hellmer J, Wahrenberg H, Arner P . Stability over time of adrenergic sensitivity in isolated human fat cells. Int J Obes Relat Metab Disord 1992; 16: 23–28.

    CAS  PubMed  Google Scholar 

  22. Seda O, Sedova L, Kren V, Krenova D, Kazdova L, Hamet P . Genetic analysis of metabolic syndrome X in the new experimental inbred model, polydactylous rat strain. Journal of Hypertension 2002; 20 (Suppl 4): S65.

    Google Scholar 

  23. Seda O, Kazdova L, Krenova D, Kren V . Rosiglitazone improves insulin resistance, lipid profile and promotes adiposity in genetic model of metabolic syndrome X. Folia Biol (Praha) 2002; 48: 237–241.

    CAS  Google Scholar 

  24. Rodondi N, Darioli R, Ramelet AA, Hohl D, Lenain V, Perdrix J, Wietlisbach V, Riesen WF, Walther T, Medinger L, Nicod P, Desvergne B, Mooser V . High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study. Ann Intern Med 2002; 136: 582–589.

    Article  CAS  PubMed  Google Scholar 

  25. Mukherjee R, Davies PJ, Crombie DL . Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 1997; 386: 407–410.

    Article  CAS  PubMed  Google Scholar 

  26. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart J . Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98: 2088–2093.

    Article  CAS  PubMed  Google Scholar 

  27. Heller F, Harvengt C . Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipidaemic subjects. Eur J Clin Pharmacol 1983; 23: 57–63.

    Article  Google Scholar 

  28. Waterworth DM, Ribalta J, Nicaud V, Dallongeville J, Humphries SE, Talmud P . ApoCIII gene variants modulate postprandial response to both glucose and fat tolerance tests. Circulation 1999; 99: 1872–1877.

    Article  CAS  PubMed  Google Scholar 

  29. Waterworth DM, Talmud PJ, Luan J, Flavell DM, Byrne CD, Humphries SE, Wareham NJ . Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men. Biochim Biophys Acta 2003; 1637: 200–206.

    Article  CAS  PubMed  Google Scholar 

  30. Coste H, Rodriguez JC . Orphan nuclear hormone receptor Rev-erbalpha regulates the human apolipoprotein CIII promoter. J Biol Chem 2002; 277: 27120–27129.

    Article  CAS  PubMed  Google Scholar 

  31. Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM . An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 2001; 294: 169–173.

    Article  CAS  PubMed  Google Scholar 

  32. Seda O, Sedova L . New apolipoprotein A-V: comparative genomics meets metabolism. Physiol Res 2003; 52: 141–146.

    CAS  PubMed  Google Scholar 

  33. Vu-Dac N, Gervois P, Jakel H, Nowak M, Bauge E, Dehondt H, Staels B, Pennacchio LA, Rubin EM, Fruchart-Najib J, Fruchart JC . Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to PPAR alpha activators. J Biol Chem 2003; 278: 17982–17985.

    Article  CAS  PubMed  Google Scholar 

  34. Vrana A, Fabry P, Poledne R, Kazdova L . Effects of the hypolipidemic drugs clofibrate and gemfibrozil on palmitate and glucose oxidation by the isolated rat diaphragm. Adv Physiol Sci 1981; 35: 515–521.

    CAS  Google Scholar 

  35. Lock EA, Mitchell AM, Elcombe CR . Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol 1989; 29: 145–163.

    Article  CAS  PubMed  Google Scholar 

  36. Chaput E, Saladin R, Silvestre M, Edgar AD . Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun 2000; 271: 445–450.

    Article  CAS  PubMed  Google Scholar 

  37. Koh EH, Kim MS, Park JY, Kim HS, Youn JY, Park HS, Youn JH, Lee KU . Proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation. Diabetes 2003; 52: 2331–2337.

    Article  CAS  PubMed  Google Scholar 

  38. Mancini FP, Lanni A, Sabatino L, Moreno M, Giannino A, Contaldo F, Colantuoni V, Goglia F . Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett 2001; 491: 154–158.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by following grants: No. 301/04/0248, No. 204/98/K015 from the Grant Agency of the Czech Republic and 6678-3 from the Internal Grant Agency of the Ministry of Health of Czech Republic.

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Correspondence to L Kazdova.

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Sedova, L., Seda, O., Krenova, D. et al. Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome. Int J Obes 28, 719–725 (2004). https://doi.org/10.1038/sj.ijo.0802613

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