Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release – potential insight into mechanism of action.

Liu J, Gorski J, Gold SJ, Chen D, Chen S, Forrest G, Itoh Y, Marsh D, McLaren D, Shen Z, Sonatore L, Carballo-Jane E, Craw S, Guan X, Karanam B, Sakaki J, Szeto D, Tong X, Xiao J, Yoshimoto R, Yu H, Balkovec J, Pinto S.
Journal   Obesity
Species  
Analytes Measured   GLP-1
Matrix Tested   Plasma
Year   2012
Volume  
Page Numbers  
Application   Metabolic
Abstract
Acyl coenzyme A: diacylglycerol acyltransferase 1(DGAT1), a key enzyme involved in the final committed step of triglyceride (TG) synthesis, has been implicated as a crucial regulator of dietary fat absorption, insulin sensitivity and body weight. In this report, we describe the identification, characterization and mechanism of action of novel, potent and selective DGAT1 inhibitors (compound K and L). Membrane-based enzyme and cellular functional assays indicated that these compounds are potent and specific inhibitors of DGAT1 activity. Compound K dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies, in established diet-induced obese (DIO) wild type (wt) and Dgat1 -/- mice, confirmed that the effects of compound K on body weight loss and food intake are mechanism-based. In addition, compound K and L markedly altered incretin peptide release following oral fat challenge. Dual-labeling immunohistochemical studies with mouse intestinal tissues demonstrate lack of detectable levels of DGAT1 immunoreactivity in enteroendocrine cells, suggesting that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Furthermore, 13C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC) through alternative carbon channeling. Taken together, these data provide insight into the underlying mechanism of DGAT1 inhibition and further support DGAT1 as a key regulator of metabolic pathways.

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