During the preparation of the manuscript, the file conversion process led to the introduction of errors in the Methods section. The correct temperatures and procedures are listed below.Measurement of desaturation index. Fatty acid methyl esters were identified with an Agilent 6890 gas chromatograph connected to an HP-5 column (30 m × 0.32 mm × 0.25 µM film thickness) connected to a flame ionization detector set at 250°C. The column and the injector temperature were set to 50°C. The column temperature was increased to 150°C at 4°C/min, increased to 200°C at 3°C/min, held at 200°C for 25 minutes, and then increased to 225°C at 25°C/min and held at 225°C for 10 minutes. Under these conditions, the ∆9-16:1, 16:0, ∆9-18:1, and 18:0 methyl esters eluted at 14. 2, 14.8, 19.4, and 20.2 minutes, respectively. The desaturation index was calculated as the ratios of ∆9-16:1/16:0 and ∆9-18:1/18:0.We regret these errors.

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.

Effective therapies for the treatment of obesity, a key element of metabolic syndrome, are urgently needed but currently lacking. Stearoyl-CoA desaturase-1 (SCD1) is the rate-limiting enzyme catalyzing the conversion of saturated long-chain fatty acids into monounsaturated fatty acids, which are major components of triglycerides. In the current study, we tested the efficacy of pharmacological inhibition of SCD1 in controlling lipogenesis and body weight in mice. SCD1-specific antisense oligonucleotide inhibitors (ASOs) reduced SCD1 expression, reduced fatty acid synthesis and secretion, and increased fatty acid oxidization in primary mouse hepatocytes. Treatment of mice with SCD1 ASOs resulted in prevention of diet-induced obesity with concomitant reductions in SCD1 expression and the ratio of oleate to stearoyl-CoA in tissues and plasma. These changes correlated with reduced body adiposity, hepatomegaly and steatosis, and postprandial plasma insulin and glucose levels. Furthermore, SCD1 ASOs reduced de novo fatty acid synthesis, decreased expression of lipogenic genes, and increased expression of genes promoting energy expenditure in liver and adipose tissues. Thus, SCD1 inhibition represents a new target for the treatment of obesity and related metabolic disorders.

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Steroid Sa-reductase (EC 1.3.1.22) catalyzes the reduction of testosterone to dihydrotestosterone. The Sareductase found in human scalp has been compared with the enzyme found in prostate. The scalp reductase has a broad pH optimum centered at pH 7.0. This is distinctiy different from the pH optimum of 5.5 observed with the prostatic form of the enzyme. These enzymes also differ in the K.. for testosterone, which is 25-fold higher for the scalp reductase. The most significant difference between the two enzymes is their affinity for inhibitors. Two 4-azasteroids and a 3-carboxyandrostadiene are potent inhibitors of the prostatic reductase but are weak inhibitors of the scalp reductase. In contrast, several N-4-methylazasteroids are good inhibitors of the scalp reductase. These findings support a proposal that different isozymes of 5a-reductase may exist in scalp and prostate. The scalp reductase was also compared to 5a-reductase 1, one of the two enzymes recently cloned from human prostate [Andersson, S.