Details

Autor(en) / Beteiligte

• Wu, Margaret
• Singh, Sheo B
• Wang, Jun
• Chung, Christine C
• Salituro, Gino
• Karanam, Bindhu V
• Lee, Sang Ho
• Powles, Maryann
• Ellsworth, Kenneth P
• Lassman, Michael E
• Miller, Corey
• Myers, Robert W
• Tota, Michael R
• Zhang, Bei B
• Li, Cai

Titel

Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2011-03, Vol.108 (13), p.5378-5383

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2011

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.