Changing the binding mode to peroxisome proliferator activated receptor (PPAR) alpha/gamma: a new ligand with improved antidiabetic and antiobesity properties

PPARs are ligand activated transcription factors playing a key role in lipid, glucose and energy metabolism. PPAR agonists are used as hypolipidemic and antidiabetic agents, however since these ligands have shown side effects, the hunt for selective PPAR modulators avoiding adverse reactions is still open. By a transfection based screening we identified LT175 that binds and activates both PPAR and subtypes. The 3D structures of PPAR/LT175 complex reveals a new binding mode with a distinct coactivator recruitment profile. In transcription assays with PPRE-Luc reporter mice, LT175 activates PPAR program in target tissues. In high fat fed mice, LT175 ameliorates the metabolic profile and reduces visceral adiposity. Circulating levels of adiponectin increases while plasma insulin decreases. LT175 enhances the expression of target genes in the liver and adipose tissue. We also observed increased brown fat mass that contributes to decrease body weight via fat burning an effect secondary to an increased FGF-21 expression. Altogether, we demonstrate that LT175 is a lead compound with favorable effects on glucose and lipid metabolism that could be developed to treat diabetes and obesity Funded by FP6 LSHM-CT-2006-037498 from the European Community to MC and The Giovanni Armenise-Harvard Foundation career development grant to N