ABSTRACT Aim Activation of peroxisome proliferator-activated receptor δ (PPARδ) subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. We aim to explore the effects of peroxisome proliferator-activated receptor δ (PPARδ) subtypes on serum lipid profiles in obese rhesus monkey, especially evaluate the efficacy of investigational new drug (HS00098). Methods: First, a prototype of obese rhesus monkey was established by continuously feeding test animals a high fat diet for 2 months. Fifteen obese rhesus monkeys were randomly divided into 3 groups, and the 2 test groups were treated with GW 501516 and HS00098. The test groups were administered doses of 0.3 mg/kg for 1 month, then with 1 mg/kg for 1 month, and finally with 3 mg/kg for 1 month. The control group received placebo treatment. In each experiment, the body weight of each animal was measured and recorded initially and prior to changing the dose of the drug each month. The total cholesterol, blood glucose, triglyceride, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum Apo-A1, Apo-B100 and insulin were tested. Results: The average body weight gain of the GW501516 and HS00098 groups was significantly lower than that of the control group. The group receiving the HS00098 treatment had a higher signifycant increase in high density lipoprotein and apo-A1 (P < 0.05) than the control monkeys, while the total cholesterol, triglycerides, low density lipoproteins, apo-B100, and insulin (P < 0.05 or P < 0.01) were significantly decreased. Compared with GW50-1516, the effects of HS00098 on serum lipid profiles in diet-induced obese rhesus monkeys are more obvious. Conclusion: These results suggested that the investigational drug (HS00098) can effectively reduce body weight, blood lipid and blood sugar levels of diet-induced obese rhesus monkeys.
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Luo, Q. , Zeng, W. , Chen, Z. , Cheng, A. , Wang, M. , Shen, Y. , Zhu, C. and Bi, F. (2012) The effect of PPARδ agonists (HS00098) on serum lipid profiles in diet-induced obese rhesus monkeys. Journal of Biomedical Science and Engineering, 5, 439-447. doi: 10.4236/jbise.2012.58056.
 WHO. Obesity: preventing and managing the global epidemic: report of WHO consultation. Tech. Rep. WHO Consultation on Obesity, Geneva, Switzerland, 1999:884.
 Eckardstein A. von and Assmann G. Prevention of coronary heart disease by raising high-density lipoprotein cholesterol? Current Opinion in Lipidology, 2000,11(6):627–637.
 James P. T., Rigby N., and Leach R. The obesity epidemic, metabolic syndrome and future prevention strategies. European Journal of Cardiovascular Prevention and Rehabilitation, 2004,11(1):3–8.
 Liberopoulos E. N., Mikhailidis D. P., and Elisaf M. S. Diagnosis and management of the metabolic syndrome in obesity. Obesity Reviews, 2005,6(4):283–296.
 Nammi S., Koka S., Chinnala K. M., and Boini K. M. Obesity: an overview on its current perspectives and treatment options. Nutrition Journal, 2004,3:3.
 Korner J. and Aronne L. J. Pharmacological approaches to weight reduction: therapeutic targets. Journal of Clinical Endocrinology and Metabolism, 2004,89(6):2616–2621.
 Cota D. and Woods S. C. The role of the endocannabinoid system in the regulation of energy homeostasis. Current Opinion in Endocrinology and Diabetes, 2005,12(5):338–351.
 Evans R. M., Barish G. D., and Wang Y.-X. PPARs and the complex journey to obesity,” Nature Medicine, 2004,10(4):355–361.
 Willson T. M., Brown P. J., Sternbach D. D., and Henke B. R. The PPARs: from orphan receptors to drug discovery. Journal of Medicinal Chemistry, 2000,43(4):527–550.
 Fajas L., Fruchart J.-C., and Auwerx J. Transcriptional control of adipogenesis. Current Opinion in Cell Biology, 1998,10(2):165–173.
 Braissant O., Foufelle F., Scotto C., Dauca M., and Wahli W.Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and –γ in the adult rat. Endocrinology, 1996,137(1):354–366.
 Oliver W. R., Shenk J. L., Snaith M. R., Russell C.S, Plunket K.D, Bodkin N.L et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proceedings of the National Academy of Sciences of the United States of America, 2001,98(9):5306–5311.
 Wang Y.X., Lee C.H., Tiep S., Yu R.T., Ham J.Y., Kang H.J., et al. Peroxisome proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell, 2003,113(2):159–170.
 Wang Y. X., Zhang C. L., Yu R. T., Cho H.K., Nelson M.C., et al. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biology, 2004,2(10):e294.
 Brown P. J., D Winegar. A., Plunket K. D., Moore L.B., Lewis M.C., Wilson J.G., et al. A ureid-othioisobutyric acid (GW9578) is a subtype-selective PPARα agonist with potent lipid-lowering activity. Journal of Medicinal Chemistry, 1999,42(19):3785–3788.
 Yang B.C., Brown K. K., Chen L.H., Carrick K.M., Clifton L.G., Mcnulty J.A., et al. Serum adiponectin as a biomarker for in vivo PPARγ activation and PPARγ agonist-induced efficacy on insulin sensitization/lipid lowering in rats. BMC Pharmacology, 2004,4(1):23.
 Henke B. R., Blanchard S. G., Brackeen M. F. N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. Journal of Medicinal Chemistry, 1998,41(25):5020–5036.
 The Ministry of Science and Technology of the People’s Republic of China. Guidance Suggestions for the Care and Use of Laboratory Animals. 2006-09-30.
 OECD. Test Guideline 409. Repeated Dose 90-day Oral Toxicity Study in Non-rodents. In: OECD Guidelines for the Testing of Chemicals. Organisation for Economic Cooperation & Development, Paris. 1998.
 Okasaki K, Funato M, Kashima M, Nakama M, Inoue K, Hiura T, et al. Twenty-Six-Week Repeat-Dose toxicity study of a recombinant human granulocyte colony-stimulating factor derivative (Nartograstim) in cynomolgus monkeys. Toxicol Sci, 2002, 65(2):246-55
 Butenhoff J, Costa G, Elcombe C. Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months. Toxicological sciences, 2002,69:244-257.
 Rockwood GA, Duniho SM, Briscoe CM Toxicity in rhesus monkeys following administration of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-5-(1-hexyloxy)-6-methoxy-4-methylquinoline (WR242511). Journal of medical toxicology, 2008,4(3):157.
 Buse J. B, Klonoff D. C, Nielsen L. L, Guan X, Bowlus C.L, Holcombe J.H, et al.. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clinical Therapeutics, 2007,29(1):139–153.
 Zhang F., Lavan B., and Gregoire F. M. Peroxisome proliferator-activated receptors as attractive antiobesity targets. Drug News and Perspectives, 2004,17(10):661–669.
 Fredenrich A. and Grimaldi P.A. PPARδ: an uncompletely known nuclear receptor. Diabetes and Metabolism, 2005,31(1):23–27.
 Luquet S., Lopez-Soriano J., Holst D., Gaudel C., Chantal J.P , Alexandre F., et al. Roles of peroxisome proliferator-activated receptor δ (PPARδ) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome. Biochimie, 2004,86(11):833–837.
 Shin H. D., Park B. L., Kim L. H., Jung H.S., Cho Y.M., Moon M.K.,et al. Genetic polymorphisms in peroxisome proliferator-activated receptor δ associated with obesity. Diabetes, 2004,53(3):847–851.
 Muurling M., Mensink R. P., Pijl H., Romijn J. A., Havekes L. M., and Voshol P. J. Rosiglitazone improves muscle insulin sensitivity, irrespective of increased triglyceride content, in ob/ob mice. Metabolism, 2003,52(8):1078–1083.
 Leibowitz M. D., Fi′evet C., Hennuyer N., et al. Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Letters, 2000,473(3):333–336.
 Lee C.H., Olson P., Hevener A., Mehl I., Chong L.W., Olefsky J.M., et al. PPARδ regulates glucose metabolism and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America, 2006,103(9):3444–3449.
 Graham TL, Mookherjee C, Suckling KE, CN AP, Patel L. The PPAR delta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis, 2005;181:29–37.
 Kang K, Hatano B, Lee CH. PPAR delta Agonists and Metabolic Diseases. Curr Atheroscler Rep, 2007;9:72–7.
 Tanaka T. Activation of peroxisome proliferator-activated receptor delta induces fatty acid betaoxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A, 2003,100:15924–9.
 Lichtenstein A. H., Kennedy E., Barrier P., Ernst N. D., Grundy S. M., Leveille G. A., et al. Nutr. Rev. 1998,56:S3–S28.
 Grundy S. M. Effects of Crystalline Nicotinic Acid-Induced Hepatic Dysfunction on Serum Low-Density Lipoprotein Cholesterol and Lecithin Cholesteryl Acyl Transferase. Am. J. Cardiol. 1998,81(6):805-807(3).
 Ginsberg H. N. Insulin resistance and cardiovascular disease. J. Clin. Invest. 2000,106, 453–458.
 Marais A. D. Therapeutic modulation of low-density lipoprotein size. Curr. Opin. Lipidol. 2000,11(6):597–602.
 Tall A. R. & Wang N. Tangier disease as a test of the reverse cholesterol transport hypothesis. J. Clin. Invest. 2000,106:1205–1207.
 Kharroubi I, Lee CH, Hekerman P, Darville MI, Evans RM, Eizirik DL, et al. BCL-6: a possible missing link for anti-inflammatory PPAR-delta signalling in pancreatic beta cells. Diabetologia, 2006;49:2350–8.