1. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes
- Author
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Margaret Wu, Cai Li, Robert W. Myers, Michael R. Tota, Michael E. Lassman, Christine C. Chung, Maryann Powles, Corey N. Miller, Jun Wang, Bindhu V. Karanam, Gino Salituro, Sheo B. Singh, Kenneth P. Ellsworth, Bei B. Zhang, and Sang Ho Lee
- Subjects
Platensimycin ,Adamantane ,Biology ,Carbohydrate metabolism ,chemistry.chemical_compound ,Mice ,Anti-Infective Agents ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Hypoglycemic Agents ,Aminobenzoates ,Anilides ,Beta oxidation ,Fatty acid synthesis ,Multidisciplinary ,Fatty liver ,Fatty Acids ,Biological Sciences ,medicine.disease ,Mice, Mutant Strains ,Cerulenin ,Fatty Liver ,Fatty acid synthase ,Disease Models, Animal ,Sterols ,Glucose ,chemistry ,Biochemistry ,Liver ,Lipogenesis ,biology.protein ,Fatty Acid Synthases ,Oxidation-Reduction - Abstract
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.
- Published
- 2011