Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Nov 15, 2017; 8(4): 161-175
Published online Nov 15, 2017. doi: 10.4291/wjgp.v8.i4.161
Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion
Benjamin S Maciejewski, Tara B Manion, Claire M Steppan
Benjamin S Maciejewski, Tara B Manion, Claire M Steppan, Pfizer Worldwide Research and Development, Cardiovascular and Metabolic Diseases Research Unit, Cambridge, MA 02139, United States
Claire M Steppan, Pfizer Inc., Groton, CT 06340, United States
Author contributions: Maciejewski BS, Manion TB and Steppan CM substantially contributed to the conception and design of the study, analysis and interpretation of data; Maciejewski BS and Manion TB contributed to the study acquisition; Maciejewski BS and Steppan CM drafted the article and made critical revisions related to the intellectual content of the manuscript and approved the final version of the article published.
Supported by Pfizer Inc.
Institutional review board statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Pfizer Inc.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Pfizer Inc. (IACUC protocol number: GTN-16169-2011).
Conflict-of-interest statement: All authors were employees of Pfizer Inc. during the conduct of these studies. To the best of our knowledge, no conflict of interest exists.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Claire M Steppan, PhD, Associate Research Fellow, Pfizer Inc., Eastern Point Road, Groton, CT 06340, United States. claire.m.steppan@pfizer.com
Telephone: +1-860-4413774
Received: January 29, 2017
Peer-review started: February 13, 2017
First decision: July 10, 2017
Revised: July 25, 2017
Accepted: September 4, 2017
Article in press: September 5, 2017
Published online: November 15, 2017
Processing time: 287 Days and 13.4 Hours
Abstract
AIM

To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) plays in postprandial gut peptide secretion and signaling.

METHODS

The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge. Following a lipid challenge, plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h. Incretin hormones [glucagon like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose dependent insulinotropic polypeptide (GIP)] were then quantitated. The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice. Additionally, a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition. To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition, other interventions [inhibitors of dipeptidyl peptidase-IV (sitagliptin), pancreatic lipase (Orlistat), GPR119 knockout mice] were evaluated.

RESULTS

DGAT1 deficient mice and wildtype C57/BL6J mice were lipid challenged and levels of both active and total GLP-1 in the plasma were increased. This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice. Furthermore, PF-04620110 was able to dose responsively increase GLP-1 and PYY, but blunt GIP at all doses of PF-04620110 during lipid challenge. Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1. In contrast, in a combination study with Orlistat, the ability of PF-04620110 to elicit an enhanced incretin response was abrogated. To further explore this observation, GPR119 knockout mice were evaluated. In response to a lipid challenge, GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY. However, PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.

CONCLUSION

Collectively, these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.

Keywords: Glucagon-like peptide-1; Peptide tyrosine-tyrosine; Glucose independent insulinotropic peptide; Acyl-CoA:diacylglycerol acyltransferase-1; Incretin

Core tip: Pharmacological Inhibition of diacylglycerol acyltransferase-1 (DGAT1) and insights into postprandial gut peptide secretion” describes studies that evaluate the effects of loss of DGAT1 function either pharmacologically or genetically on the incretin response. We demonstrate a synergistic effect on the incretin response with the combination of a DGAT1 inhibitor and sitagliptin, a dipeptidyl peptidase-IV inhibitor. Additional studies performed address the molecular mechanism by with pharmacological inhibition of DGAT1 results in increased gut peptide secretion. These data provide insight into the role of DGAT1 in the intestinal hormone release and its potential as a drug target for the treatment of type 2 diabetes.