Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice

Naoto Tsuda; Shin Kumadaki; Chika Higashi; Makoto Ozawa; Mikihiko Shinozaki; Yutaka Kato; Koutarou Hoshida; Satomi Kikuchi; Yoshihisa Nakano; Yoshihiro Ogawa; Shoji Furusako

doi:10.1371/journal.pone.0112027

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice

PLoS One. 2014 Nov 18;9(11):e112027. doi: 10.1371/journal.pone.0112027. eCollection 2014.

Affiliations

¹ Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan; Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
² Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
³ Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Objective: Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final committed step in triglyceride biosynthesis. DGAT1 null mice are known to be resistant to diet-induced obesity, and more insulin sensitive relative to the wild-type; however, the mice exhibit abnormalities in the skin. This work determined whether the intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice.

Design and methods: We synthesized 2 DGAT1 inhibitors: Compound A, described in the patent application from the Japan Tobacco, and Compound B (A-922500), reported by Abbott Laboratories. Both compounds were evaluated for inhibitory activities against DGAT1 enzymes and effects on the skin in mice in vivo. Compound B was further investigated for effects on obesity and insulin resistance in diet-induced-obese (DIO) mice.

Results: The 2 compounds comparably inhibited the DGAT1 enzyme activity and the cellular triglyceride synthesis in vitro, while they showed different distribution patterns in mice in vivo. Compound A, which distributed systemically, caused skin aberrations, while Compound B, which preferentially distributed to the intestine, improved obesity and insulin resistance without skin aberrations in DIO mice.

Conclusions: Our results suggest that the intestine is the key tissue in which DGAT1 plays a role in promoting obesity and insulin resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biphenyl Compounds / adverse effects
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / pharmacokinetics
Biphenyl Compounds / therapeutic use*
Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
Diacylglycerol O-Acyltransferase / metabolism
Enzyme Inhibitors / adverse effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / therapeutic use*
HT29 Cells
Hep G2 Cells
Humans
Insulin Resistance*
Intestinal Mucosa / metabolism
Intestines / drug effects*
Male
Mice
Mice, Inbred C57BL
Obesity / drug therapy*
Phenylurea Compounds / adverse effects
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / pharmacokinetics
Phenylurea Compounds / therapeutic use*
Skin / drug effects
Tissue Distribution

Substances

(IR,2R)-2-(4'-(3-phenyl-ureido)-biphenyl-4-carbonyl)cyclopentanecarboxylic acid
Biphenyl Compounds
Enzyme Inhibitors
Phenylurea Compounds
Dgat1 protein, mouse
Diacylglycerol O-Acyltransferase

Grants and funding

Mochida Pharmaceutical provided all funds for this work. NT, SK, CH, MO, MS, YK, KH, SK, YN, and SF are current employees of Mochida Pharmaceutical and may own stock or hold stock options in Mochida Pharmaceutical. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.