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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Biphenyl Compounds, Diacylglycerol O-Acyltransferase, Enzyme Inhibitors, HT29 Cells, Hep G2 Cells, Humans, Insulin Resistance, Intestinal Mucosa, Intestines, Male, Mice, Mice, Inbred C57BL, Obesity, Phenylurea Compounds, Skin, Tissue Distribution.
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Does intestine-targeted DGAT1 inhibition improve obesity and insulin resistance without skin aberrations in mice? Context: 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. 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. 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.
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Our results suggest that the intestine is the key tissue in which DGAT1 plays a role in promoting obesity and insulin resistance. Final Decision: yes