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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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. Copyright:

Original languageEnglish
Article numbere112027
JournalPloS one
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 18 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Tsuda, N., Kumadaki, S., Higashi, C., Ozawa, M., Shinozaki, M., Kato, Y., Hoshida, K., Kikuchi, S., Nakano, Y., Ogawa, Y., & Furusako, S. (2014). Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice. PloS one, 9(11), [e112027]. https://doi.org/10.1371/journal.pone.0112027