The Fatty Acid Synthase Inhibitor Platensimycin Improves Insulin Resistance without Inducing Liver Steatosis in Mice and Monkeys

Abstract

ObjectivesPlatensimycin (PTM) is a natural antibiotic produced by Streptomyces platensis that selectively inhibits bacterial and mammalian fatty acid synthase (FAS) without affecting synthesis of other lipids. Recently, we reported that oral administration of PTM in mouse models (db/db and db/+) with high de novo lipogenesis (DNL) tone inhibited DNL and enhanced glucose oxidation, which in turn led to net reduction of liver triglycerides (TG), reduced ambient glucose, and improved insulin sensitivity. The present study was conducted to explore translatability and the therapeutic potential of FAS inhibition for the treatment of diabetes in humans.MethodsWe tested PTM in animal models with different DNL tones, i.e. intrinsic synthesis rates, which vary among species and are regulated by nutritional and disease states, and confirmed glucose-lowering efficacy of PTM in lean NHPs with quantitation of liver lipid by MRS imaging. To understand the direct effect of PTM on liver metabolism, we performed ex vivo liver perfusion study to compare FAS inhibitor and carnitine palmitoyltransferase 1 (CPT1) inhibitor.ResultsThe efficacy of PTM is generally reproduced in preclinical models with DNL tones comparable to humans, including lean and established diet-induced obese (eDIO) mice as well as non-human primates (NHPs). Similar effects of PTM on DNL reduction were observed in lean and type 2 diabetic rhesus and lean cynomolgus monkeys after acute and chronic treatment of PTM. Mechanistically, PTM lowers plasma glucose in part by enhancing hepatic glucose uptake and glycolysis. Teglicar, a CPT1 inhibitor, has similar effects on glucose uptake and glycolysis. In sharp contrast, Teglicar but not PTM significantly increased hepatic TG production, thus caused liver steatosis in eDIO mice.ConclusionsThese findings demonstrate unique properties of PTM and provide proof-of-concept of FAS inhibition having potential utility for the treatment of diabetes and related metabolic disorders.

Short-term strength training reduces gluconeogenesis and NAFLD in obese mice

“…As ACC, FAS inhibition was also investigated to combat NAFLD. Chronic use of FAS inhibitor reduced lipogenesis in both mice and monkeys (Singh et al 2016). Herein, the short-term strength training reduced the levels of mRNA and FAS contend, reinforcing the efficiency of this protocol in downregulating the synthesis of lipids in the liver of obese animals, regardless of body weight change.…”

Dietary Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) Operate by Different Mechanisms to Modulate Hepatic Steatosis and Hyperinsulemia in fa/fa Zucker Rats

“…The present study demonstrates that both DHA and EPA prevent the accumulation of liver lipid relative to baseline levels over eight weeks, but that DHA is more effective than EPA for reducing FAS levels, promoting smaller lipid droplets and improving insulin resistance in the fa/fa rodent model of genetic obesity, insulin resistance, and hepatic steatosis. Likewise, an inhibitor of mammalian FAS has been shown to reduce hepatic lipids and improve insulin sensitivity in various preclinical models [25]. The parallel changes in absolute liver weight and liver lipid content support the evidence that DHA and EPA reduced hepatic lipid deposition.…”

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

“…During the preparation of this manuscript, PTM was shown to preferentially accumulate in the liver of monkeys, with high concentrations in urine and bile. 6 …”

“…As a lead compound for the treatment of diabetes, liver steatosis, and other metabolic disorders, 3,6 enrichment of PTM in liver may be desirable; rapid degradation of PTM, however, is not. We uncovered three sites of liability for PTM and PTN: (i) hydrolysis of the amide bond (ii) glucurondiation of the ADHBA moiety, and (iii) oxidation of the hydrophobic ketolide moiety.…”

“…2–4 PTM is also a lead compound for the treatment of diabetes and related metabolic disorders as it is a potent and highly selective inhibitor of mammalian fatty acid synthase. 5,6 …”