The core technology of Yonsei University is to provide promising drug candidates or functional food ingredients of plant origin for the treatment or prevention of hyperlipidemia, fatty liver, insulin resistance and/or obesity. Novel uses of phytochemicals, including piperonal, piperine, cinchonine, scopolin, and carvacrol and extracts of Litchi semen, preventing and treating obesity and metabolic diseases were discovered. The above mentioned phytochemicals or plant have been used as food additives of ingredients in Korea and Western countries, and therefore are expected to possess little or no adverse side effects. Effective dose ranges and LD50 values of these drug candidates are known. The molecular mechanisms underlying the protective effects of these phytochemicals against obesity and metabolic diseases include increased thermogenesis and fatty acid oxidation along with reduced adipogenesis in the visceral fat and hepatic tissues of obese mice.
Background and unmet needs
Changes in life styles and living environments result in a pathogenic increase of visceral fat obesity in modern people. Frequent occurrence of visceral obesity in turn leads to a rapid increase in development of metabolic syndromes which are accompanied by diabetes, hypertension, lipid metabolism disorders, insulin resistance and the like. These attendant diseases mutually interact to increase the pathogenic risk of individual conditions and are common diseases which are associated with a variety of metabolic changes such as senescence, stress conditions, compromised immune function and the like. According to the 2005 National Health and Nutrition Survey, 32% of Korean adults above the age of 20 were found to suffer from obesity (35.2% of male adults and 28.3% of female adults). Then, such an increase in the overweight and obese population contributes to a rise in the prevalence rate of chronic diseases. For example, according to the 2005 survey data on Korean people over the age of 30, the prevalence rates of hypertension, diabetes, and hypercholesterolemia were significantly higher than in other countries.
Orlistat, which is currently used as an anti-obesity drug, suffers from adverse side effects such as steatorrhea (fatty stools), enteric gas production, and flatus. Another anti-obesity drug, sibutramine, is also known to have adverse side effects such as headache, thirst, anorexia, insomnia, constipation and the like. Further, orlistat inhibits absorption of vitamin D and E, whereas administration of phentermine and sibutramine results in adverse side effects such as an increased heart rate/palpitations, vertigo, and the like. Although most current obesity therapies are focused on reducing caloric intake, recent data suggest that increasing cellular energy expenditure (bioenergetics) may be an attractive alternative approach for overcoming obesity. An energy expenditure system that includes a thermogenic mechanism to burn off excess fat to re-establish energy balance has been envisioned. In addition, carnitine palmitoyl-transferase 1 and fatty acid synthase function at a metabolic crossroads between energy consumption and storage, therefore, activity through the fatty acid metabolic pathway reflects the energetic state of the cell.
Recently, values and demands for herbal or natural medicines are increasing in view of adverse side effects of synthetic drugs and limitations of Western medicine in treating chronic diseases. To cope with this trend, the present inventor has discovered several drug candidates effective in treating obesity and metabolic diseases from a variety of wild or volunteer plants.
Discovery and Achievements
- Molecular target: PPARα,βγ, and LXR
- Mechanism of action: increased thermogenesis; increased fatty acid oxidation; reduced adipogenesis; increased glucose transporter 4 translocation
- Indication(s) proposed for the compound(s): reduces body weight and visceral fat-pad weights without affecting food intake; reduces blood cholesterol, triglyceride and free fatty acid levels; improves fatty liver(reduces hepatic triglyceride, cholesterol and fatty acid levels and reduces blood GOT and GPT activities); improves insulin resistance index and reduces fasting blood glucose level in mice with high fat diet-induced obesity.
- Potency of the compound in relevant in vitro assays:
EC50 value of piperine inhibiting preadipocyte differentiation in 3T3-L1 cells is 120 μM.
- Potency of the compound when given to animals, route of administration:
1) Supplementation of high-fat diet with 0.05% piperine for 10 weeks resulted in 68% reduction in body weight gain, 66% decrease in the total visceral fat-pad weights and 50~84% reductions in blood lipid levels compared to those for mice fed the high-fat diet..
2) Oral administration of piperine (50 mg/kg BW) by gavarge resulted in weight reduction equivalent to that observed in mice administered sibutramine (10 mg/kg BW)
- Toxicology and safety report summary:
Piperonal, piperine, carvacrol, cinchonine, and scopolin are phytochemicals found in edible plants and have been used for food additives for long years. No adverse side effects have been reporte