Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

Abstract PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an a...

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Autores principales:	Gloria Brusotti, Roberta Montanari, Davide Capelli, Giulia Cattaneo, Antonio Laghezza, Paolo Tortorella, Fulvio Loiodice, Franck Peiretti, Bernadette Bonardo, Alessandro Paiardini, Enrica Calleri, Giorgio Pochetti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c974505d82c84893809cac091a690522
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spelling	oai:doaj.org-article:c974505d82c84893809cac091a6905222021-12-02T11:40:33ZBetulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis10.1038/s41598-017-05666-62045-2322https://doaj.org/article/c974505d82c84893809cac091a6905222017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05666-6https://doaj.org/toc/2045-2322Abstract PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARγ and PPARα antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARγ sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARγ, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases.Gloria BrusottiRoberta MontanariDavide CapelliGiulia CattaneoAntonio LaghezzaPaolo TortorellaFulvio LoiodiceFranck PeirettiBernadette BonardoAlessandro PaiardiniEnrica CalleriGiorgio PochettiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gloria Brusotti Roberta Montanari Davide Capelli Giulia Cattaneo Antonio Laghezza Paolo Tortorella Fulvio Loiodice Franck Peiretti Bernadette Bonardo Alessandro Paiardini Enrica Calleri Giorgio Pochetti Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
description	Abstract PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARγ and PPARα antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARγ sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARγ, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases.
format	article
author	Gloria Brusotti Roberta Montanari Davide Capelli Giulia Cattaneo Antonio Laghezza Paolo Tortorella Fulvio Loiodice Franck Peiretti Bernadette Bonardo Alessandro Paiardini Enrica Calleri Giorgio Pochetti
author_facet	Gloria Brusotti Roberta Montanari Davide Capelli Giulia Cattaneo Antonio Laghezza Paolo Tortorella Fulvio Loiodice Franck Peiretti Bernadette Bonardo Alessandro Paiardini Enrica Calleri Giorgio Pochetti
author_sort	Gloria Brusotti
title	Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
title_short	Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
title_full	Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
title_fullStr	Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
title_full_unstemmed	Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
title_sort	betulinic acid is a pparγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c974505d82c84893809cac091a690522
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Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis

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