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

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.

Fig. 1.

Effect of platensimycin (A), two widely used FAS inhibitors (cerulenin and C75, B and C), and the ACC inhibitor TOFA (D) on fatty acid and sterol synthesis in rat primary hepatocytes.

Fig. 2.

Platensimycin preferentially distributes to the liver following oral dosing (n = 3) (A) and inhibits fatty acid synthesis in the liver, but not in adipose tissue (WAT) (n = 5) (B). db/db mice were used. For A, PTM was dosed orally at 100 mpk; for B, PTM was administered via i.p. injection at the doses indicated. Lower limits of detection were 0.0045, 0.045, and 0.009 μM for plasma, brain, and liver. For fatty acid synthesis measurements, the [³H]H₂0 incorporation method was used.

Fig. 3.

Platensimycin levels in liver are positively correlated with DNL inhibition in db/db mice. (A) rate of hepatic lipogenesis as a function of time and PTM dosages; (B–D) correlation of liver PTM levels and lipogenesis inhibition at 2, 4, and 8 h. Veh, vehicle.

Fig. 4.

Platensimycin inhibits fatty acid oxidation in primary rat hepatocytes. n = 3 wells. Data are expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle.

Fig. 5.

Platensimycin reduces fatty acid oxidation (A) and increases whole-body glucose oxidation (B) in vivo. db/db mice of 14.5 wk of age were used (n = 7 mice per group). *P < 0.05, **P < 0.01 versus vehicle.

Fig. 6.

Platensimycin increases malonyl-CoA but not acetyl-CoA or CoA levels in the livers of db/db mice at 1 h postdosing. Mice received an oral dose of platensimycin as indicated at 9:00 AM and food was removed. Livers were collected and quickly frozen at 1, 4, and 8 h postdose. n = 5 per group. *P < 0.05, **P < 0.01 versus vehicle.

Fig. 7.

Chronic platensimycin treatment leads to a reduction of liver triglyceride levels (A) and increased insulin sensitivity as determined by an insulin tolerance test (B). Dosed animals were db/+ mice fed a high-fructose diet (n = 8 mice per group). *P < 0.05, ***P < 0.001 versus vehicle.

Fig. 8.

Chronic treatment of db/db mice with platensimycin lowers plasma glucose and plasma ketone bodies, and leads to a trend toward liver TG reduction. (A) Time course of plasma glucose changes. (B) Change in glucose as a percentage of vehicle as a function of treatment duration. Vehicle glucose was set as 100%, and glucose levels in the treated groups were normalized to the respective vehicle groups. (C) Terminal liver TG levels. (D) Terminal plasma β-HBA level (n = 7–8 mice per group). *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle.