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



We 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.



The 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.



These 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.
Departments of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Sheo B
SB
Singh
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Ling
L
Kang
Department of Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Andrea R
AR
Nawrocki
Department of Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Dan
D
Zhou
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Margaret
M
Wu
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Stephen
S
Previs
Department of Imaging and Biomarker, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Corey
C
Miller
Department of Imaging and Biomarker, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Haiying
H
Liu
Department of Translational Imaging Biomarkers, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA, 19486, United States of America.
Catherine D G
CD
Hines
Department of PKPD, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Maria
M
Madeira
Department of Imaging and Biomarker, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Jin
J
Cao
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Kithsiri
K
Herath
Larry D
LD
Spears
Clay F
Semenkovich
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Liangsu
L
Wang
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
David E
DE
Kelley
Department of Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Cai
C
Li
Department of Cardiometabolic Disease, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ, 07033, United States of America.
Hong-Ping
0000-0002-2282-3193
HP
Guan
Biochem J. 1975 Aug;150(2):167-73
1237298
Biochim Biophys Acta. 1990 Nov 12;1047(2):168-74
2248973
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5378-83
21389266
Nature. 2006 May 18;441(7091):358-61
16710421
J Lipid Res. 2013 Oct;54(10):2615-22
23828778
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8695-9
7567999
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
14512514
J Cardiovasc Pharmacol. 2011 Jul;58(1):102-10
21558881
J Clin Invest. 2005 May;115(5):1343-51
15864352
Nutrition. 2016 Nov-Dec;32(11-12):1254-67
27346714
Prostaglandins Leukot Essent Fatty Acids. 2015 Jul;98:7-14
25910408
Biol Mass Spectrom. 1991 Jun;20(6):392-6
1653617
Anal Biochem. 2010 Sep 15;404(2):235-7
20488158
J Clin Invest. 2008 Mar;118(3):829-38
18317565
Methods Enzymol. 2015;561:331-58
26358910
Diabetes. 2011 Feb;60(2):644-51
21270274
Cell Metab. 2005 May;1(5):309-22
16054078
Annu Rev Biochem. 1983;52:537-79
6137188
Diabetologia. 2003 Dec;46(12):1662-8
14614559
Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E884-94
18682535
J Lipid Res. 2015 Nov;56(11):2183-95
26373568
Am J Physiol. 1998 Feb;274(2 Pt 2):R524-8
9486313
J Lipid Res. 2009 Apr;50 Suppl:S138-43
19047759
Toxicol Pathol. 2010 Apr;38(3):393-401
20215584
Nutrients. 2014 Dec 10;6(12 ):5679-703
25514388
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6358-63
12738878
Bioorg Med Chem. 2006 Mar 1;14(5):1506-17
16256355
J Mass Spectrom. 1997 Jan;32(1):81-6
9008871
Science. 2011 Jun 24;332(6037):1519-23
21700865
Int J Clin Exp Pathol. 2010 Mar 25;3(5):505-14
20606731