title: Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases.
abstract: Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacological studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compound, T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 weeks caused weight loss, reduction in serum and liver triglycerides, and improved insulin sensitivity. In addition to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small molecule inhibitor for DGAT1 and suggests that pharmacological inhibition of DGAT1 holds promise in treating diverse metabolic disorders.
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140. Electronic address: jingsong.cao@novartis.com.
authors: Jingsong
authors: J
authors: Cao
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Yingjiang
authors: Y
authors: Zhou
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Haibing
authors: H
authors: Peng
authors: Screening Sciences, Pfizer, Collegeville, Pennsylvania 19426.
authors: Xinyi
authors: X
authors: Huang
authors: Screening Sciences, Pfizer, Collegeville, Pennsylvania 19426.
authors: Shannon
authors: S
authors: Stahler
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Vipin
authors: V
authors: Suri
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Ariful
authors: A
authors: Qadri
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Tiffany
authors: T
authors: Gareski
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Juli
authors: J
authors: Jones
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Seung
authors: S
authors: Hahm
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: Mylene
authors: M
authors: Perreault
authors: Exploratory Medicinal Chemistry, Pfizer, Cambridge, Massachusetts 02140.
authors: John
authors: J
authors: McKew
authors: Discovery Pharmacokinetics, Pfizer, Andover, Massachusetts 01810.
authors: Mengxiao
authors: M
authors: Shi
authors: Discovery Pharmacokinetics, Pfizer, Andover, Massachusetts 01810.
authors: Xin
authors: X
authors: Xu
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140.
authors: James F
authors: JF
authors: Tobin
authors: Biocorrection Research Unit, Pfizer, Cambridge, Massachusetts 02140. Electronic address: gimeno_ruth@lilly.com.
authors: Ruth E
authors: RE
authors: Gimeno
mesh_terms: D041721:3T3-L1 Cells; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008820:Mice, Obese; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D014280:Triglycerides; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase