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Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release—Potential insight into mechanism of action
Author(s) -
Liu Jinqi,
Gorski Judith N.,
Gold Stephen J.,
Chen Dunlu,
Chen Shirley,
Forrest Gail,
Itoh Yoshiki,
Marsh Donald J.,
McLaren David G.,
Shen Zhu,
Sonatore Lisa,
CarballoJane Ester,
Craw Stephanie,
Guan Xiaoming,
Karanam Bindhu,
Sakaki Junichi,
Szeto Daphne,
Tong Xinchun,
Xiao Jianying,
Yoshimoto Ryo,
Yu Hong,
Roddy Thomas P.,
Balkovec James,
Pinto Shirly
Publication year - 2013
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.20193
Subject(s) - diacylglycerol kinase , mechanism of action , chemistry , peptide , lipid metabolism , endocrinology , medicine , biochemistry , enzyme , biology , in vitro , protein kinase c
Objective Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L . Design and 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). Conclusion 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.