The peroxisome proliferator activated receptor-gamma (PPARg) is an attractive target for therapeutic intervention, as modulation of PPARg-regulated pathways is potentially beneficial in a number of disease areas. This review provides an overview of what is known about the biology of PPARg, and an indication of what progress has been made towards drug development in several therapy areas. As well as efficacy, the safety of drugs is of course an important issue, and a substantial volume of preclinical and clinical information has already accumulated for PPARg agonists. Here we discuss some of the major toxicology issues with PPARg agonists, and give a perspective on likely issues concerning the development of PPARgmodulators in the future.
Willson TM , Brown PJ , Sternbach DD , Henke BR . The PPARs: from orphan receptors to drug discovery . J Med Chem2000; 43: 527–550 .
2.
Lehmann JM , Moore LB , Smith-Oliver TA , et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) . J Biol Chem1995; 270: 12953–12956 .
3.
Montague CT , O’Rahilly S.The perils of portliness: causes and consequences of visceral adiposity . Diabetes2000; 49: 883–888 .
4.
Schoonjans K , Peinado-Onsurbe J , Lefebvre AM , et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene . EMBO J1996; 15: 5336–5348 .
5.
Hotamisligil GS , Peraldi P , Budavari A , et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance . Science1996; 271: 665–668 .
6.
Hauner H , Petruschke T , Russ M , et al. Effects of tumour necrosis factor alpha (TNF alpha) on glucose transport and lipid metabolism of newly-differentiated human fat cells in cell culture . Diabetologia1995; 38: 764–771 .
7.
Rosenbaum SE , Greenberg AS . The short-and long-term effects of tumor necrosis factor-alpha and BRL 49653 on peroxisome proliferator-activated receptor (PPAR)gamma2 gene expression and other adipocyte genes . Mol Endocrinol1998; 12: 1150–1160 .
8.
Muller G , Ertl J , Gerl M , Preibisch G.Leptin impairs metabolic actions of insulin in isolated rat adipocytes . J Biol Chem1997; 272: 10585–10593 .
9.
Pallett AL , Morton NM , Cawthorne MA , Emilsson V.Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets . Biochem Biophys Res Commun1997; 238: 267–270 .
10.
Burant CF , Sreenan S , Hirano K , et al. Troglitazone action is independent of adipose tissue . J Clin Invest1997; 100: 2900–2908 .
11.
Masuda K , Okamoto Y , Tsuura Y , et al. Effects of Troglitazone (CS-045) on insulin secretion in isolated rat pancreatic islets and HIT cells: an insulinotropic mechanism distinct from glibenclamide . Diabetologia1995; 38: 24–30 .
12.
Shimabukuro M , Zhou YT , Lee Y , Unger RH . Induction of uncoupling protein-2 mRNA by troglitazone in the pancreatic islets of Zucker diabetic fatty rats . Biochem Biophys Res Commun1997; 237: 359–361 .
13.
Kwon G , Xu G , Marshall CA , McDaniel ML . Tumor necrosis factor alpha-induced pancreatic beta-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-Delta12,14-prostaglandin J2 and aminoguanidine. A role for peroxisome proliferator-activated receptor gamma activation and inos expression . J Biol Chem1999; 274: 18702–18708 .
14.
Shimabukuro M , Zhou YT , Lee Y , Unger RH . Troglita-zone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats . J Biol Chem1998; 273: 3547–3550 .
15.
Komers R , Vrana A.Thiazolidinediones–tools for the research of metabolic syndrome X . Physiol Res1998; 47: 215–225 .
16.
Ricote M , Li AC , Willson TM , et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation . Nature1998; 391: 79–82 .
17.
Nagy L , Tontonoz P , Alvarez JG , et al. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma . Cell1998; 93: 229–240 .
18.
Tontonoz P , Nagy L , Alvarez JG , et al. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL . Cell1998; 93: 241–252 .
19.
Desreumaux P , Ernst O , Geboes K , et al. Inflammatory alterations in mesenteric adipose tissue in Crohn's disease . Gastroenterology1999; 117: 73–81 .
20.
Su CG , Wen X , Bailey ST , et al. A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response . J Clin Invest1999; 104: 383–389 .
21.
Demetri GD , Fletcher CD , Mueller E , et al. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma . Proc Natl Acad Sci USA1999; 96: 3951–3956 .
22.
Elstner E , Muller C , Koshizuka K , et al. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice . Proc Natl Acad Sci USA1998; 95: 8806–8811 .
23.
Kubota T , Koshizuka K , Williamson EA , et al. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo . Cancer Res1998; 58: 3344–3352 .
24.
Sarraf P , Mueller E , Smith WM , et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer . Mol Cell1999; 3: 799–804 .
25.
Lefebvre AM , Chen I , Desreumaux P , et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/ + mice . Nat Med1998; 4: 1053–1057 .
26.
Breider MA , Gough AW , Haskins JR , et al. Troglitazoneinduced heart and adipose tissue cell proliferation in mice . Toxicol Pathol1999; 27: 545–552 .
27.
Pickavance LC , Tadayyon M , Widdowson PS , et al. Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution . Br J Pharmacol1999; 128: 1570–1576 .
28.
Ghazzi MN , Perez JE , Antonucci TK , et al. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group . Diabetes1997; 46: 433–439 .
29.
Ramachandran V , Kostrubsky VE , Komoroski BJ , et al. Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes . Drug Metab Dispos1999; 27: 1194–1199 .
30.
Jones SA , Moore LB , Shenk JL , et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution . Mol Endocrinol2000; 14: 27–39 .
31.
Shibuya A , Watanabe M , Fujita Y , et al. An autopsy case of troglitazone-induced fulminant hepatitis . Diabetes Care1998; 21: 2140–2143 .
32.
Ott P , Ranek L , Young MA . Pharmacokinetics of troglitazone, a PPAR-gamma agonist, in patients with hepatic insufficiency . Eur J Clin Pharmacol1998; 54: 567–571 .
33.
Al-Salman J , Arjomand H , Kemp DG , Mittal M.Hepatocellular injury in a patient receiving rosiglita-zone. A case report . Ann Intern Med2000; 132: 121–124 .
34.
Scheen AJ . Thiazolidinediones and liver toxicity . Diabetes Metab2001; 27: 305–313 .
35.
Gimble JM , Robinson CE , Wu X , et al. Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells . Mol Pharmacol1996; 50: 1087–1094 .
36.
Lecka-Czernik B , Gubrij I , Moerman EJ , et al. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2 . J Cell Biochem1999; 74: 357–371 .
37.
Okazaki R , Toriumi M , Fukumoto S , et al. Thiazolidinediones inhibit osteoclast-like cell formation and bone resorption in vitro . Endocrinology1999; 140: 5060–5065 .
38.
Smith CL , Nawaz Z , O’Malley BW . Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen . Mol Endocrinol1997; 11: 657–666 .
39.
Reginato MJ , Bailey ST , Krakow SL , et al. A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor gamma-activating properties . J Biol Chem1998; 273: 32679–32684 .
40.
Kubota N , Terauchi Y , Miki H , et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance . Mol Cell1999; 4: 597–609 .
41.
Barak Y , Nelson MC , Ong ES , et al. PPAR gamma is required for placental, cardiac, and adipose tissue development . Mol Cell1999; 4: 585–595 .
