Indole derivatives are known to have beneficial biological activities due to their anticancer, antioxidant, anti-inflammatory, and antitubercular effects. In this study, I presented that a CF3-allylated indole, ((E) -1-(pyrimidin- 2-yl)-2- (4,4,4- trifluorobut- 2- enyl) -1H- indole), suppresssed the intracellular lipid content and lowered the expression levels of CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FASN), and sterol regulatory element-binding proteins (SREBP1) in 3T3-L1 adipocyte cells. The anti-adipogenic effect of CF3-allylated indole predominantly showed at the early stage of adipocyte differentiation by enhancing the intracellular cyclic adenosine monophosphate (cAMP) levels and phosphorylation of protein kinase A catalytic subunit (PKAc) and adenosine monophosphate-activated protein kinase alpha (AMPKα). On the other hand, knockdown of PKAc or induction with PKA inhibitor (H89) attenuated the anti-adipogenic effects of CF3-allylated indole on adipocyte differentiation and PPARγ expression. This indicates that CF3-allylated indole suppresses the early phase of adipocyte differentiation by enhancing PKA and AMPKα phosphorylation which induces downregulated expression of adipogenic genes in 3T3-L1 cells, suggesting the possibility of suppressing the early phase of adipogenesis obesity.
YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) is a pyrimidine derivative which exerts anti-inflammatory, anti-emetogenic and anti-asthmatic effects. However, the effects of YM976 on adipocyte differentiation have not been determined yet. Here, I found that YM976 significantly lowered the lipid accumulation without cytotoxicity and reduced the expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) as well as their lipogenic regulators including fatty acid-binding protein 4 (FABP4) and fatty acid synthase (FASN) in 3T3-L1 cells. YM976 inhibited adipocyte differentiation from the initial stage to the last stage of adipocyte differentiation. Furthermore, intracellular cAMP levels were elevated by YM976 treatment resulting in increased adenosine monophosphate-activated protein kinase alpha (AMPKα) phosphorylation. Conversely, silencing with si-RNA against AMPKα or treatment of Compound C (AMPK inhibitor) reversed in part the inhibitory effects of YM976 on adipogenesis and PPARγ transcriptional activity. Thus, YM976 can be a novel potential compound for controlling lipid accumulation as well as formation of adipocytes which is critical for the development of obesity.