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Changing the binding mode to peroxisome proliferator activated receptor (PPAR) alpha/gamma: a new ligand with improved antidiabetic and antiobesity properties
Author(s) -
Mitro Nico,
Gilardi Federica,
Giudici Marco,
Loiodice Fulvio,
Fracchiolla Giuseppe,
Laghezza Antonio,
Pochetti Giorgio,
Lavecchia Antonio,
Guerrini Uliano,
Tremoli Elena,
Rando Gianpaolo,
Maggi Adriana,
Novellino Ettore,
Crestani Maurizio
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.659.11
Subject(s) - coactivator , peroxisome proliferator activated receptor , endocrinology , adipose tissue , medicine , receptor , nuclear receptor , adiponectin , lipid metabolism , adipogenesis , transcription factor , transfection , chemistry , reporter gene , peroxisome , biology , insulin , insulin resistance , biochemistry , gene expression , gene
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 PPARα and γ subtypes. The 3D structures of PPARγ/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 NM