Abstract

A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand ( S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of ( S)-6 to the canonical site. However, ( S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, ( S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

Autore Pugliese

• Laghezza Antonio , Loiodice Fulvio , Piemontese Luca , Tortorella Paolo

Tutti gli autori

• LAGHEZZA A.;LAVECCHIA A.;LOIODICE F.;PIEMONTESE L.;TORTORELLA P.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2018

ISSN

0022-2623

ISBN

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Numero di citazioni Wos

Nessuna citazione

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Settori ERC

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Codici ASJC

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