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The bromodomain inhibitor N-methyl pyrrolidone reduced fat accumulation in an ovariectomized rat model
Bebeka Gjoksi1, Chafik Ghayor2, Indranil Bhattacharya3
1Oral Biotechnology & Bioengineering, Center for Dental Medicine, Cranio-Maxillofacial and Oral Surgery, University of Zurich, Zurich, Switzerland ; Cartilage Engineering + Regeneration Laboratory, ETH Zurich, Zurich, Switzerland.
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.
