The bromodomain inhibitor N-methyl pyrrolidone reduced fat accumulation in an ovariectomized rat model.
BACKGROUND
Weight gain is one of the consequences of estrogen deficiency and constitutes a major health problem. The present study highlights the effects of N-methyl pyrrolidone (NMP) on adipogenesis in osteoporosis induced by estrogen deficiency in an ovariectomized rat model.


RESULTS
Ovariectomy resulted in body weight gain, increased femoral marrow adipocytes, and hypertrophic adipocytes in white adipose tissue, distorted serum leptin, and TNF-α and PPARγ levels. Treatment with NMP normalized these parameters similar to the control group. In vitro, NMP inhibited the differentiation of 3T3-L1 pre-adipocytes and hMSCs, indicating its anti-adipogenic effect. Moreover, PPARγ was significantly reduced with NMP treatment in in vivo and in vitro experiments. NMP inhibited BRD2 and BRD4 binding in an AlphaScreen assay, with an IC50 of 3 and 4 mM, respectively. The effect of NMP was consistent with its role as a bromodomain inhibitor.


CONCLUSIONS
Our data indicates that NMP inhibits the adipogenic effect of estrogen deficiency at the level of PPARγ expression by BRD4 inhibition.
Oral Biotechnology & Bioengineering, Center for Dental Medicine, Cranio-Maxillofacial and Oral Surgery, University of Zurich, Zurich, Switzerland ; Cartilage Engineering + Regeneration Laboratory, ETH Zurich, Zurich, Switzerland.
Bebeka
B
Gjoksi
Oral Biotechnology & Bioengineering, Center for Dental Medicine, Cranio-Maxillofacial and Oral Surgery, University of Zurich, Zurich, Switzerland.
Chafik
C
Ghayor
Oral Biotechnology & Bioengineering, Center for Dental Medicine, Cranio-Maxillofacial and Oral Surgery, University of Zurich, Zurich, Switzerland ; Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
Indranil
I
Bhattacharya
Cartilage Engineering + Regeneration Laboratory, ETH Zurich, Zurich, Switzerland ; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland.
Marcy
M
Zenobi-Wong
Oral Biotechnology & Bioengineering, Center for Dental Medicine, Cranio-Maxillofacial and Oral Surgery, University of Zurich, Zurich, Switzerland ; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland ; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Franz E
FE
Weber
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010024:Osteoporosis / Q000150:complications / Q000209:etiology* / Q000378:metabolism; D010052:Ovariectomy / Q000009:adverse effects*; D011485:Protein Binding / Q000187:drug effects; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*; D000092468:Bromodomain Containing Proteins
D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D011760:Pyrrolidinones; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C038678:N-methylpyrrolidone
Adipocytes; Epigenetic modulator; Osteoporosis; Small inhibitor molecule