Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage.
Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs.
†Cheminformatics and Nutrition Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus de Sescelades, 43007 Tarragona, Spain.|‡Nutrition and Health Research Group, Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Avinguda Universitat, 1, 43204 Reus, Spain.
Santiago
S
Garcia-Vallvé
§Computer-Aided Drug Design Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, United States.
Laura
L
Guasch
†Cheminformatics and Nutrition Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus de Sescelades, 43007 Tarragona, Spain.
Sarah
S
Tomas-Hernández
‡Nutrition and Health Research Group, Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Avinguda Universitat, 1, 43204 Reus, Spain.
Josep Maria
JM
del Bas
∥INRA, UMR866 Dynamique Musculaire et Métabolisme, F-34060 Montpellier Université Montpellier 1, F-34000 Montpellier - Université Montpellier 2, F-34000 Montpellier, France.
Vincent
V
Ollendorff
‡Nutrition and Health Research Group, Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Avinguda Universitat, 1, 43204 Reus, Spain.|⊥Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus de Sescelades, 43007 Tarragona, Spain.
Lluís
L
Arola
†Cheminformatics and Nutrition Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus de Sescelades, 43007 Tarragona, Spain.|‡Nutrition and Health Research Group, Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Avinguda Universitat, 1, 43204 Reus, Spain.
Gerard
G
Pujadas
†Cheminformatics and Nutrition Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus de Sescelades, 43007 Tarragona, Spain.
Miquel
M
Mulero
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship
D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma