title: Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release--potential insight into mechanism of action.
abstract: OBJECTIVE
  Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L.
  
  
  METHODS
  Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models.
  
  
  RESULTS
  Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC).
  
  
  CONCLUSIONS
  Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Jinqi
authors.initials: J
authors.lastname: Liu
authors.forename: Judith N
authors.initials: JN
authors.lastname: Gorski
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gold
authors.forename: Dunlu
authors.initials: D
authors.lastname: Chen
authors.forename: Shirley
authors.initials: S
authors.lastname: Chen
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Itoh
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Lisa
authors.initials: L
authors.lastname: Sonatore
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Stephanie
authors.initials: S
authors.lastname: Craw
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Guan
authors.forename: Bindhu
authors.initials: B
authors.lastname: Karanam
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakaki
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.forename: James
authors.initials: J
authors.lastname: Balkovec
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
mesh_terms: D000818:Animals; D001823:Body Composition; D001835:Body Weight / Q000187:drug effects*; D002853:Chromatography, Liquid; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D036145:Ginsenosides / Q000494:pharmacology; D019073:HT29 Cells; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077403:Orlistat; D019518:Postprandial Period / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000097:blood
chemical_list: D051048:Diacylglycerol O-Acyltransferase; D036145:Ginsenosides; D006728:Hormones; D007783:Lactones; D000077403:Orlistat; D014280:Triglycerides; C112772:ginsenoside compound K; C494882:Dgat1 protein, mouse