대사성질환 완화에 관여하는 PPARγ/AMPK 이중 작용제의 효능 분석에 관한 연구

Abstract

Insulin resistance, known as a primary cause of obesity and metabolic disorder, has the close relation with type 2 diabetes, hyperlipidemia, hyperglycemia, high cholesterol, atherosclerosis and cardiovascular disease. Especially, lipid metabolite plays an important role in pathogenesis and progression of insulin resistance. Therefore, control of lipid metabolism is important to improve insulin resistance and metabolic diseases. Cleistocalyx operculatus is a plant widely distributed in southern Asia, and its water extract is commonly used to relieve heat and to prevent and treat diabetes. 2,4-dihydroxy-6-methoxy-3,5-dimethylchalcone (DMC) is a major compound of the extract and is reported to have anti-tumor, anti-oxidative, and anti-inflammatory effects. However, the underlying mechanism of improvement in diabetes and metabolic diseases has not been elucidated. To carry out this study, we isolated DMC from Cleistocalyx operculatus extract to increasing PPARγ activity. Compared to rosiglitazone, DMC showed a lower PPARγ transcriptional activity and 10 times lower binding activity to the PPARγ LBD. However, fatty acid oxidation rate by DMC was higher than that by rosiglitazone. Interestingly, DMC is useful to inhibit adipocyte differentiation, which is totally different from rosiglitazone. In addition, DMC increases phosphorylation of AMPK, one of the major targets of diabetes and metabolic diseases. Compared to AICAR and metformin, well-known AMPK activators, DMC could increase AMPK activity, even at much lower concentrations. Next, DMC was administrated to the high-fat fed mice, and the effects of DMC on insulin resistance were determined. DMC improves insulin resistance as effectively as pioglitazone did. Interestingly, DMC treatment reduced fat tissue and showed weight loss compared to the pioglitazone treatment. Taken together, these results indicate that, DMC will provide great help to improve lipid metabolism and insulin resistance without side effects such as obesity.