To examine the effects of novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist C333H on insulin resistance and lipid metabolism.
An established dual-luciferase reporter gene assay system was used in vitro to test the activity of C333H with respect to the transcription of human PPARα and PPARγ. A preadipocyte differentiation assay and reverse transcription-polymerase chain reaction were used to detect the functional activities of C333H. In db/db mice, the effects of C333H were investigated with respect to lowering of blood glucose and lipid levels.
C333H was determined to be a novel PPARα/γ dual agonist because it strongly induced luciferase activity on human PPARα and PPARγ, promoting the differentiation of preadipocytes to adipocytes, and functioning in upregulating the expression of some glucose and lipid metabolic target genes of the PPAR. In addition, C333H efficiently reduced blood lipid and glucose concentrations in db/db diabetic mice.
C333H has dual action on both PPARα and PPARγ, and might be of interest for the amelioration of lipid metabolic disorders and insulin resistance associated with type 2 diabetes.
Grundy SM, Barnett JP . Metabolic and health complications of obesity. Dis Mon 1990; 36: 641–713.
Ginsberg H, Plutzky J, Sobel E . Review of metabolic and cardiovascular effects of oral antidiabetic agents: beyond glucose level lowering. J Cardivasc Risk 1999; 6: 337–46.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–9.
Schoonjans K, Martin G, Staels B, Auwerx J . Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997; 8: 159–66.
Willson TM, Brown PJ, Sternbach DD, Henke BR . The PPARs: from orphan receptors to drug discovery. J Med Chem 2000 43: 527–50.
Bole PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, et al. Effects of pioglitazone and rosiglitazone on blood lipid level and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002 24: 378–96.
Chaput E, Saladin R, Sliverstre M, Edgar AD . Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun 2000; 271: 445–50.
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: 2088–93.
Sadoeski I, Ptashne M . A vector for expressing GAL4 (1–147) fusion in mammalian cells. Nucl Acids Res 1989; 17: 7539.
Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, et al. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARγ and RXRα. Nucl Acids Res 1994; 22: 5628–34.
Camp HS, Li O, Wise SC . Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539–47.
Vazquez M, Silvestre JS, Prous JR . Experimental approaches to study PPARγ agonists as antidiabetic drugs. Methods Find Exp Clin Pharmacol 2002; 24: 515–23.
Fruchart JC . Peroxisome proliferator-activated receptor-α activation and high-density lipoprotein metabolism. Am J Cardiol 2001; 88: 24N–9N.
Lowell BB . PPARγ: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999; 99: 230–53.
Okuno A, Tamemoto H, Tobe K . Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese zucker rats. J Clin Invest 1998; 101: 1354–61.
Tontonoz P, Hu E, Spiegelman BM . Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994; 79: 1147–56.
Schoonjans K, Peinado-Onsurbe J, Lefebvre AM . PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO 1996; 15: 5336–48.
Wu Z, Xie Y, Morrison RF, Bucher NLR, Farmer SR . PPARγ induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPα during the conversion of 3T3 fibroblasts in adipocytes. J Clin Invest 1998; 101: 22–32.
Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A . Peroxisome proliferator-activated receptor gene expression in human tissues. J Clin Invest 1997; 99: 2416–22.
Kruszynska YT, Mukherjee R, Jow L, Dana S, Paterniti JR, Olefsky JM . Skeletal muscle peroxisome proliferation-activated receptor-γ expression in obesity and non-insulin-dependent diabetes mellitus. J Clin Invest 1998; 101: 543–8.
Escher P, Wahli W . Peroxisome proliferator-activated receptor insight into multiple cellular function. Mutat Res 2000; 448: 121–38.
Project supported by the National High Technology Research and Development Program of China (863 Program, No 2003AA235010) and the Beijing Technological Program (No H030230070110).
About this article
Cite this article
Xu, C., Wang, Ll., Liu, Hy. et al. C333H, a novel PPARα/γ dual agonist, has beneficial effects on insulin resistance and lipid metabolism. Acta Pharmacol Sin 27, 223–228 (2006). https://doi.org/10.1111/j.1745-7254.2006.00263.x
- peroxisome proliferator-activated receptor
- insulin resistance
- lipid metabolism
Oleanolic acid induces a dual agonist action on PPARγ/α and GLUT4 translocation: A pentacyclic triterpene for dyslipidemia and type 2 diabetes
European Journal of Pharmacology (2020)
Peroxisome Proliferator-Activated Receptors and Caloric Restriction—Common Pathways Affecting Metabolism, Health, and Longevity
Regulation of peroxisome proliferator-activated receptors (PPAR) α and -γ of rat brain astrocytes in the course of activation by toll-like receptor agonists
Journal of Neurochemistry (2015)
Biochimica et Biophysica Acta (BBA) - General Subjects (2015)
Journal of Medicinal Chemistry (2012)