AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect

• Published in: Bioorganic & medicinal chemistry letters 2010-07, Vol.20 (14), p.4128-4131
• Main Authors: Nguyen, Phi Hung, Le, Thi Van Thu, Kang, Hu Won, Chae, Jooyoung, Kim, Sang Kyum, Kwon, Kwang-iI, Seo, Dae Bang, Lee, Sang Jun, Oh, Won Keun
• Format: Article
• Language: English
• Subjects: AMP-activated protein kinase (AMPK); AMP-Activated Protein Kinases - metabolism; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - isolation & purification; Anti-Obesity Agents - pharmacology; Biological and medical sciences; Enzyme Activators - chemistry; Enzyme Activators - isolation & purification; Enzyme Activators - pharmacology; General pharmacology; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Myristica fragrans; Myristica fragrans - chemistry; Myristicaceae; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Tetrahydrofuran lignans
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.067

In our program to search new AMPK activators from plants, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C1 (6), and galbacin (7) were isolated from Myristica fragrans (nutmeg). Among the isolates, compounds 1, 4, and 5 at 5μM produced strong AMPK stimulation in differentiated C2C12 cells. The active fraction containing of high content of nectandrin B showed protective effect on the increase of blood glucose and body weight in high-fat diet (HFD)-induced mice. AMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPK activators from plants, this study found that the total extract of Myristica fragrans (nutmeg) activated the AMPK enzyme in differentiated C2C12 cells. As active constituents, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C1 (6), and galbacin (7) were isolated from this extract. Among the isolates, compounds 1, 4, and 5 at 5μM produced strong AMPK stimulation in differentiated C2C12 cells. In addition, the preventive effect of a tetrahydrofuran mixture (THF) on weight gain in a diet-induced animal model was further examined. These results suggest that nutmeg and its active constituents can be used not only for the development of agents to treat obesity and possibly type-2 diabetes but may also be beneficial for other metabolic disorders.