Characterization of a Novel PPARγ/AMPK Dual Agonist Having Beneficial Effects on Metabolic Disorder

학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과 의과학전공, 2016. 2. 박경수.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.Introduction 1 Materials and methods 11 Result 28 Discussion 75 References 85 국문 초록 98Docto