Abstract
Crotadihydrofuran C (CC) from the herbs of Crotalaria albida is able to inhibit adipocyte differentiation and lipid accumulation. However, the effects of CC on obesity and metabolic disorders have not yet been elucidated. In our study, the first enantioselective synthesis of the 2-isopropenyl dihydrofuran isoflavone skeleton (CC) is described. The convenient and efficient synthetic protocols developed skilfully solve the problems of the ortho-para directing group and Suzuki coupling reaction using a boronic acid pinacol ester that was more stable and easy to obtain. Furthermore, CC treatment of high-fat diet (HFD)-fed obese mice remarkably reduced their body weight, fat mass, and lipid level as well as improved insulin resistance and non-alcoholic fatty liver disease (NAFLD). A TR-FRET assay showed that CC was specifically bound to PPARγ LBD, which was further confirmed by the molecular docking study. These results suggest that CC could be a useful and potential natural product for treating metabolic diseases, including obesity, hyperlipidemia insulin resistance and NAFLD, without toxic side-effects.
Highlights
Crotadihydrofuran C (CC) from the herbs of Crotalaria albida is able to inhibit adipocyte differentiation and lipid accumulation
The nuclear receptor peroxisome proliferator-activated receptor γ(PPARγ)is a ligand-activated transcription factor, which is involved in lipogenesis as well as glucose and energy homeostasis, and it has been identified as a therapeutic target for metabolic diseases[8,9,10]
These results indicate that the inhibition of PPARγactivity could be beneficial to prevent and treat obesity and obesity-related metabolic diseases, and it may even be superior to activation in terms of obesity based on fat formation and lipogenesis
Summary
Crotadihydrofuran C (CC) from the herbs of Crotalaria albida is able to inhibit adipocyte differentiation and lipid accumulation. A TR-FRET assay showed that CC was bound to PPARγ LBD, which was further confirmed by the molecular docking study These results suggest that CC could be a useful and potential natural product for treating metabolic diseases, including obesity, hyperlipidemia insulin resistance and NAFLD, without toxic side-effects. Obesity is caused by an imbalance between energy expenditure and food consumption and is frequently associated with the development of serious chronic diseases such as atherosclerosis, hypertension, insulin resistance, hyperlipidemia and fatty liver[1,2,3,4]. Recent studies have highlighted that PPARγantagonists ameliorated high-fat diet (HFD)-induced obesity, insulin resistance and fatty liver disease by inhibiting lipogenesis[15,16,17,18,19,20,21]. Our data indicated that CC treatment could improve obesity, insulin resistance, hyperlipidemia and non-alcoholic fatty liver disease (NAFLD) disease in diet-induced obesity (DIO) mice as a novel PPARγantagonist
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