4-O-methylascochlorin suppresses differentiation of 3T3-L1 preadipocytes by inhibiting PPARγ expression through regulation of AMPK/mTOR signaling pathways

Obesity increases the risk of developing many chronic diseases, including type 2 diabetes and certain cancers, and is thereby associated with premature death. The present study was conducted to identify the inhibitory effect of the ascochlorin derivative 4-O-methylascochlorin (MAC) on the differentiation of 3T3-L1 preadipocytes. MAC suppressed the differentiation of 3T3-L1 preadipocytes and inhibited the expression of adipocyte differentiation marker genes, FABP4, PPAR gamma and C/EBP alpha. In addition, we found that the inhibitory effects of MAC on differentiation of 3T3-L1 preadipocytes were caused by suppression of mTORC1 via inhibition of mTOR/p7056K/4E-BP1 phosphorylation and activation of Raptor phosphorylation. MAC also regulated the PPAR gamma expression and the mTORC1 activation by increasing AMPK phosphorylation and inhibiting PI3K/Akt, which suggest that MAC suppresses the differentiation of 3T3-L1 adipocytes by regulating the AMPK- and PI3K-mTOR-PPAR gamma signaling pathways. Furthermore, animal model results showed that the phosphorylation of AMPK was enhanced in the liver of C57BL/6 mice intraperitoneally injected with MAC. These results indicate that MAC could be a therapeutic agent for obesity involving PPAR gamma and AMPK. (C) 2015 Elsevier Inc. All rights reserved.