Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지

Fenofibrate Inhibits Visceral Adiposity by Inhibiting UCPs in C57BL/6J Mice Fed on a High Fat Diet

  • Oh, Jaeho (Department of Life Sciences, Mokwon University) ;
  • Yoon, Michung (Department of Life Sciences, Mokwon University)
  • Received : 2012.09.06
  • Accepted : 2012.10.10
  • Published : 2012.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

We investigated to verify whether the $PPAR{\alpha}$ agonist fenofibrate regulates adipose tissue metabolism and to determine the molecular mechanism involved in this regulation. After male mice (C57BL/6J) received a high fat diet with or without fenofibrate for 6 weeks, the effects of fenofibrate on not only adipose tissue weight, visceral adipocyte size, serum lipid and glucose levels, but also the expression of uncoupling proteins (UCPs). Mice given a fenofibrate-supplemented high fat diet showed reduced both visceral and subcutaneous adipose tissue weights versus high fat diet-fed animals. The size of visceral adipocytes was significantly decreased by fenofibrate treatment. The administration of fenofibrate resulted in decreased serum levels of triglycerides, free fatty acids, and glucose. Moreover, fenofibrate up-regulated mRNA levels of visceral adipose tissue UCP2 and skeletal muscle UCP3. Therefore, our results suggest that the increases in the expression of UCPs by fenofibrate seem to suppress diet-induced visceral adiposity as well as severe hypertriglyceridemia and hyperglycemia in male mice.

Keywords

References

  1. Acin A, Rodriguez M, Rique H, Canet E, Boutin JA, Galizzi JP. Cloning and characterization of the 5' flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem Biophys Res Commun. 1999. 258: 278-283. https://doi.org/10.1006/bbrc.1999.0530
  2. Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest. 1994. 93: 2438-2446. https://doi.org/10.1172/JCI117252
  3. Bourgeois F, Alexiu A, Lemonnier D. Dietary-induced obesity: effect of dietary fats on adipose tissue cellularity in mice. Br J Nutr. 1983. 49: 17-26. https://doi.org/10.1079/BJN19830006
  4. Cabrero A, Llaverias G, Roglans N, Alegret M, Sanchez R, Adzet T, Laguna JC, Vazquez M. Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats. Biochem Biophys Res Commun. 1999. 260: 547-556. https://doi.org/10.1006/bbrc.1999.0926
  5. Cabrero A, Alegret M, Sanchez R, Adzet T, Laguna JC, Vazquez M. Peroxisome proliferator-activated receptor ${\alpha}(PPAR{\alpha})$ activators, bezafibrate and Wy-14,643, increase uncoupling protein-3 mRNA levels without modifying the mitochondrial membrane potential in primary culture of rat preadipocytes. Arch Biochem Biophys. 2000. 380: 353-359. https://doi.org/10.1006/abbi.2000.1927
  6. 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. https://doi.org/10.1006/bbrc.2000.2647
  7. Choi CS, Fillmore JJ, Kim JK, Liu ZX, Kim S, Collier EF, Kulkarni A, Distefano A, Hwang YJ, Kahn M, Chen Y, Yu C, Moore IK, Reznick RM, Higashimori T, Shulman GI. Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest. 2007. 117: 1995-2003. https://doi.org/10.1172/JCI13579
  8. Clapham JC, Arch JR, Chapman H, Haynes A, Lister C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA, Beeley LJ, Godden RJ, Herrity N, Skehel M, Changani KK, Hockings PD, Reid DG, Squires SM, Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ, Cadenas S, Buckingham JA, Brand MD, Abuin A. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature. 2000. 406: 415-418. https://doi.org/10.1038/35019082
  9. Costet P, Legendre C, More J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem. 1998. 273: 29577-29585. https://doi.org/10.1074/jbc.273.45.29577
  10. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992. 68: 879-887. https://doi.org/10.1016/0092-8674(92)90031-7
  11. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem. 2000. 275: 16638-16642. https://doi.org/10.1074/jbc.275.22.16638
  12. Hesselink MK, Mensink M, Schrauwen P. Human uncoupling protein-3 and obesity: an update. Obes Res. 2003. 11: 1429-1443. https://doi.org/10.1038/oby.2003.192
  13. Jeong S, Kim M, Han M, Lee H, Ahn J, Kim M, Song YH, Shin C, Nam KH, Kim TW, Oh GT, Yoon M. Fenofibrate prevents obesity and hypertriglyceridemia in low-density lipoprotein receptor-null mice. Metabolism. 2004a. 53: 607-613. https://doi.org/10.1016/j.metabol.2003.12.010
  14. Jeong S, Han M, Lee H, Kim M, Kim J, Nicol CJ, Kim BH, Choi JH, Nam KH, Oh GT, Yoon M. Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. Metabolism. 2004b. 53: 1284-1289. https://doi.org/10.1016/j.metabol.2004.05.003
  15. Jeong S, Choi WC, Yoon M. Effects of fenofibrate on adipogenesis in female C57BK/6J mice. J Exp Biomed Sci. 2005. 11: 1-8.
  16. Jeong S, Choi HK, Yoon M. Morphological changes in adipose and liver tissues by 17-estradiol in female ovariectomized C57BL/6 mice. J Exp Biomed Sci. 2007. 13: 99-104.
  17. Jeong S, Yoon M. Inhibition of the actions of peroxisome proliferator-activated receptor alpha on obesity by estrogen. Obesity (Silver Spring). 2007. 15: 1430-1440. https://doi.org/10.1038/oby.2007.171
  18. Jeong S, Yoon M. Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice. Exp Mol Med. 2009. 41: 397-405. https://doi.org/10.3858/emm.2009.41.6.045
  19. Kadowaki T. Insights into insulin resistance and type 2 diabetes from knockout mouse models. J Clin Invest. 2000. 106: 459-465. https://doi.org/10.1172/JCI10830
  20. Kliewer SA, Lehmann JM, Wilson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 1999. 284: 757 -760. https://doi.org/10.1126/science.284.5415.757
  21. Kopecky J, Clarke G, Enerback S, Spiegelman B, Kozak LP. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest. 1995. 96: 2914-2923. https://doi.org/10.1172/JCI118363
  22. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999. 4: 597-609. https://doi.org/10.1016/S1097-2765(00)80210-5
  23. Lentes KU, Tu N, Chen H, Winnikes U, Reinert I, Marmann G, Pirke KM. Genomic organization and mutational analysis of the human UCP2 gene, a prime candidate gene for human obesity. J Recept Signal Transduct Res. 1999. 19: 229-244. https://doi.org/10.3109/10799899909036648
  24. Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy JO, Semenkovich CF. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat Med. 2000. 6: 1115-1120. https://doi.org/10.1038/80450
  25. Liu X, Rossmeisl M, McClaine J, Riachi M, Harper ME, Kozak LP. Paradoxical resistance to diet-induced obesity in UCP1- deficient mice. J Clin Invest. 2003. 111: 399-407. https://doi.org/10.1172/JCI200315737
  26. MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB, Harper ME. Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes 2005. 54: 2343-2350. https://doi.org/10.2337/diabetes.54.8.2343
  27. 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. https://doi.org/10.1016/S0014-5793(01)02146-9
  28. Mori Y, Tokutate Y, Oana F, Matsuzawa A, Akahane S, Tajima N. Bezafibrate-induced changes over time in the expression of uncoupling protein (UCP) mRNA in the tissues: a study in spontaneously type 2 diabetic rats with visceral obesity. J Atheroscler Thromb. 2004. 11: 224-231. https://doi.org/10.5551/jat.11.224
  29. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest. 1998. 101: 1354-1361. https://doi.org/10.1172/JCI1235
  30. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996. 97: 2859 -2865. https://doi.org/10.1172/JCI118742
  31. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996. 37: 907-925.
  32. Schrauwen P, Hesselink M. UCP2 and UCP3 in muscle controlling body metabolism. J Exp Biol. 2002. 205: 2275-2285.
  33. Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its metabolic role. Int J Biochem Cell Biol. 2004. 36: 2098 -2104. https://doi.org/10.1016/j.biocel.2004.04.003
  34. Srivastava RA, Jahagirdar R, Azhar S, Sharma S, Bisgaier CL. Peroxisome proliferator-activated receptor-${\alpha}$ selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. Mol Cell Biochem. 2006. 285: 35-50. https://doi.org/10.1007/s11010-005-9053-y
  35. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998. 98: 2088-2093. https://doi.org/10.1161/01.CIR.98.19.2088
  36. Wang S, Subramaniam A, Cawthorne MA, Clapham JC. Increased fatty acid oxidation in transgenic mice overexpressing UCP3 in skeletal muscle. Diabetes Obes Metab. 2003. 5: 295-301. https://doi.org/10.1046/j.1463-1326.2003.00273.x
  37. Yoon M, Jeong S, Nicol CJ, Lee H, Han M, Kim JJ, Seo YJ, Ryu C, Oh GT. Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism. Exp Mol Med. 2002. 34: 481-488. https://doi.org/10.1038/emm.2002.67
  38. Yoon M, Jeong S, Lee H, Han M, Kang JH, Kim EY, Kim M, Oh GT. Fenofibrate improves lipid metabolism and obesity in ovariectomized LDL receptor-null mice. Biochem Biophys Res Commun. 2003. 302: 29-34. https://doi.org/10.1016/S0006-291X(03)00088-3
  39. Yoon M. The role of $PPAR{\alpha}$ in lipid metabolism and obesity: Focusing on the effects of estrogen on $PPAR{\alpha}$ actions. Pharmacol Res. 2009. 60: 151-159. https://doi.org/10.1016/j.phrs.2009.02.004