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Sci Rep. 2017 Jul 18;7(1):5777. doi: 10.1038/s41598-017-05666-6.

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

Author information

1
Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Via Taramelli 12, 27100, Pavia, Italy.
2
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015, Monterotondo Stazione, Roma, Italy.
3
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E.Orabona 4, 70126, Bari, Italy.
4
Inserm UMR 1062, Faculté de Médecine Timone, Aix-Marseille University, 27 bd Jean Moulin, 13385, Marseille, France.
5
Department of Biology and Biotechnology, Università "La Sapienza" di Roma, via dei Sardi 70, 00185, Roma, Italy.
6
Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Via Taramelli 12, 27100, Pavia, Italy. enrica.calleri@unipv.it.
7
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015, Monterotondo Stazione, Roma, Italy. giorgio.pochetti@ic.cnr.it.

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.

PMID:
28720829
PMCID:
PMC5516003
DOI:
10.1038/s41598-017-05666-6
[Indexed for MEDLINE]
Free PMC Article

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