title: Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuda
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kumadaki
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Higashi
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Shinozaki
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Koutarou
authors.initials: K
authors.lastname: Hoshida
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Discovery Research, Mochida Pharmaceutical Company Limited, Shizuoka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Furusako
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: C542909:(IR,2R)-2-(4'-(3-phenyl-ureido)-biphenyl-4-carbonyl)cyclopentanecarboxylic acid; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase