Abstract
Leptin and peroxisome proliferator-activated receptors are two important adipose tissue
factors involved in energy metabolism regulation. It has been shown that PPARγ agonists
decrease leptin levels. However, the effects of PPARα agonists on leptin have not
been investigated much. The aim of this study was to compare the effects of a PPARγ
agonist rosiglitazone (RSG) and PPARα agonist gemfibrozil (G) on body weight and serum
insulin and leptin levels in diet-induced obese rats. Male Wistar rats were divided
into six groups according to diet and drug therapy. After four weeks, serum glucose,
triglyceride, insulin and leptin levels were significantly decreased in the high-fat-fed
and RSG-treated groups compared to the group fed a high-fat diet only (162 ± 19 vs. 207 ± 34 mg/dl, 58 ± 20 vs. 112 ± 23 mg/dl, 3.1 ± 1.0 vs. 15.2 ± 4.0 ng/ml, 1.6 ± 0.5 vs. 3.6 ± 1.6 ng/ml, respectively). However, these parameters were not statistically
different in RSG animals treated with a standard diet compared to the standard diet
group. The high fat+RSG group gained much more weight compared to high-fat and high-fat+G
groups (p > 0.05). Additionally, serum glucose, insulin and leptin levels were significantly
decreased in the high-fat-fed and G-treated group compared to high-fat group (149
± 19 vs. 207 ± 34 mg/dl, 57 ± 16 vs. 112 ± 23 mg/dl, 4.3 ± 2.1 vs. 15.2 ± 4.0 ng/ml, 1.6 ± 0.4 vs. 3.6 ± 1.6 ng/ml, respectively). These results suggest that PPARα agonists may decrease
serum glucose, insulin and leptin levels as PPARγ agonists do in diet-induced obese
rats.
Key words
Diet-induced obesity - Leptin - Rosiglitazone - Gemfibrozil - PPAR
References
- 1
Flier J S.
The adipocyte: storage depot or node on the energy information superhighway.
Cell.
1995;
80
15-18
- 2
Must A, Spadano J, Coakley E H, Field A E, Colditz G, Dietz W H.
The disease burden associated with overweight and obesity.
JAMA.
1999;
282
1523-1529
- 3
Markovic T P, Jenkins A B, Campbell L V, Furler S M, Kraegen E W, Chisholm D J.
The determinants of glycemic responses to diet restriction and weight loss in obesity
and NIDDM.
Diabetes Care.
1998;
21
687-694
- 4
Kersten S.
Peroxisome proliferator activated receptors and obesity.
Eur J Pharmacol.
2002;
440
223-234
- 5
Kersten S, Desvergne B, Wahli W.
Roles of PPARs in health and disease.
Nature.
2000;
405
421-424
- 6
Knopp R H.
Drug treatment of lipid disorders.
N Engl J Med.
1999;
341
498-511
- 7
Lee C H, Olson P, Evans R M.
Minireview: Lipid Metabolism, metabolic diseases, and peroxisome proliferator-activated
receptors.
Endocrinology.
2003;
144
2201-2207
- 8
Spiegelman B M.
PPAR-γ: adipogenic regulator and thiazolidinedione receptor.
Diabetes.
1998;
47
507-514
- 9
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M.
Positional cloning of the mouse gene and its human homologue.
Nature.
1994;
372
425-432
- 10
Ahima R S, Flier J S.
Adipose tissue as an endocrine organ.
TEM.
2000;
11
327-332
- 11
Considine R V.
Regulation of leptin production.
Rev Endocr Metab Disord.
2001;
2
357-363
- 12
Walker C G, Bryson J M, Phuyal J L, Caterson I D.
Dietary modulation of circulating leptin levels: site-spesific changes in fat deposition
and ob mRNA expression.
Horm Metab Res.
2001;
34
176-181
- 13
Akiyama T, Tachibana I, Shirohara H, Watanabe N, Otsuki M.
High-fat hypercaloric diet induces obesity, glucose intolerance and hyperlipidemia
in normal adult male Wistar rat.
Diabetes Res Clin Pract.
1996;
31
27-35
- 14
Storlien L H, James D E, Burleigh K M, Chisholm D J, Kraegen E W.
Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure,
and obesity in rats.
Am J Physiol.
1986;
251
E576-E583
- 15
Johansen T, Richelsen B, Hansen H S, Din N, Malmlöf K.
Growth hormone-mediated breakdown of body fat: effects of GH on lipases in adipose
tissue and skeletal muscle of old rats fed different diets.
Horm Metab Res.
2003;
35
243-250
- 16
Masuzaki H, Ogawa Y, Hosoda K, Kawada T, Fushiki T, Nakao K.
Augmented expression of the obese gene in the adipose tissue from rats fed high-fat
diet.
Biochem Biophys Res Commun.
1995;
216
355-358
- 17
Ainslie D A, Proietto J, Fam B C, Thorburn A W.
Short-term, high-fat diets lower circulating leptin concentrations in rats.
Am J Clin Nutr.
2000;
71
438-442
- 18
Takahashi N, Patel H R, Qi Y, Dushay J, Ahima R S.
Divergent effects of leptin in mice susceptible or resistant to obesity.
Horm Metab Res.
2002;
34
691-697
- 19
Pickavance L C, Tadayyon M, Widdowson P S, Buckingham R E, Wilding J PH.
Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy
and haemodilution.
Br J Pharmacology.
1999;
128
1570-1576
- 20
Hevener A, Reichart D, Janez A, Olefsky J.
Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in
male wistar rats.
Diabetes.
2001;
50
2316-2322
- 21
Oakes N D, Camilleri S, Furler S M, Chisholm D J, Kraegen E W.
The insulin sensitizer, BRL 49 653, reduces systemic fatty acid supply and utilization
and tissue lipid availability in the rat.
Metabolism.
1997;
46
935-942
- 22
Kraegen E W, Cooney G J, Ye J, Thompson A L.
Triglycerides, fatty acids and insulin resistance - hyperinsulinemia.
Exp Clin Endocrinol Diabetes.
2001;
109
S516-S526
- 23
Saltiel A R, Olefsky J M.
Thiazolidinediones in the treatment of insulin resistance and type II diabetes.
Diabetes.
1996;
45
1661-1669
- 24
De Vos P, Lefebvre A M, Miller S G, Guerro-Millo M, Wong K, Saladin R, Hamann L G,
Staels B, Briggs M R, Auwerx J.
Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome
proliferator-activated reseptor γ.
J Clin Invest.
1996;
98
1004-1009
- 25
Wang Q, Dryden S, Frankish H M, Bing C, Pickavance L, Hopkins D, Buckingham R, Williams G.
Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49 653 (rosiglitazone)
and the possible involvement of leptin and hypothalamic neuropeptide Y.
Br J Pharmacology.
1997;
122
1405-1410
- 26
Kallen C B, Lazar M A.
Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes.
Proc Natl Acad Sci USA.
1996;
93
5793-5796
- 27
Hollenberg A N, Susulic V S, Madura J P, Zhang B, Moller D E, Tontonoz P, Sarraf P,
Spiegelman B M, Lowell B B.
Functional antagonism between CCAAT/enhancer binding protein-alpha and peroxisome
proliferator-activated receptor-gamma on the leptin promoter.
J Biol Chem.
1997;
272
5283-5290
- 28
Hardie L J, Guilhot N, Trayhurn P.
Regulation of leptin production in cultured mature white adipocytes.
Horm Metab Res.
1996;
28
685-689
- 29
Considine R V, Caro J F.
Leptin and the regulation of body weight.
Int J Biochem Cell Biol.
1997;
29
1255-1272
- 30
Chaput E, Saladin R, Silvestre M, Edgar A D.
Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body
weight.
Biochem Biophys Res Commun.
2000;
271
445-450
- 31
Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert J M, Winegar D A,
Willson T M, Fruchart J C, Berge R K, Staels B.
Peroxisome proliferator-activated receptor α activators improve insulin sensitivity
and reduce adiposity.
J Biol Chem.
2000;
275
16638-16642
- 32
Mancini F P, 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
- 33
Kochan Z, Karbowska J, Swierczynski J.
Effect of clofibrate on malic enzyme and leptin mRNAs level in rat brown and white
adipose tissue.
Horm Metab Res.
1999;
31
538-542
- 34
Rizvi F, Puri A, Bhatia G, Khanna A K, Wulff E M, Rastogi A K, Chander R.
Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model.
Biochem Biophys Res Commun.
2003;
305
215-222
- 35
Ye J M, Doyle P, Iglesias M A, Watson D G, Cooney G J, Kraegen E.
Peroxisome proliferator-activated receptor (PPAR)-α activation lowers muscle lipids
and improves insulin sensitivity in high fat-fed rats.
Diabetes.
2001;
50
411-417
F. B. Törüner
Gazi University Faculty of Medicine · Division of Endocrinology and Metabolism ·
Halit Ziya Sokak 24/8 Çankaya · 06540 · Ankara · Turkey
Phone: +90(312)214-1000, -5804 ·
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