Skip to main content

ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Endocrinology of Aging
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1432928
This article is part of the Research Topic Endocrinology of Obesity, Aging and Stress View all 12 articles

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

Provisionally accepted
James E. Blevins James E. Blevins 1,2*Mackenzie K. Honeycutt Mackenzie K. Honeycutt 1Jared Slattery Jared Slattery 1Matvey Goldberg Matvey Goldberg 1June R. Rambousek June R. Rambousek 1Edison Tsui Edison Tsui 1Andrew D. Dodson Andrew D. Dodson 1Kyra A. Shelton Kyra A. Shelton 1Therese S. Salemeh Therese S. Salemeh 1Clinton T. Elfers Clinton T. Elfers 3Kylie Chichura Kylie Chichura 4Emily F. Ashlaw Emily F. Ashlaw 4Sakeneh Zraika Sakeneh Zraika 1,2Robert P. Doyle Robert P. Doyle 4Christian Roth Christian Roth 2,4
  • 1 VA Puget Sound Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Seattle, United States
  • 2 School of Medicine, University of Washington, Seattle, Washington, United States
  • 3 Seattle Children's Research Institute, Seattle, Washington, United States
  • 4 Syracuse University, Syracuse, New York, United States

The final, formatted version of the article will be published soon.

    We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1-and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R +/+ mice and GLP-1R null (GLP-1R -/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout.Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R +/+ mice by -1.5±0.6, -1.3±0.4 and -1.9±0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R +/+ mice. These effects were absent in male and female DIO GLP-1R -/-mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R +/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R -/-mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R +/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.

    Keywords: Obesity, Multi-agonist, GLP-1, PYY, IWAT, IBAT

    Received: 15 May 2024; Accepted: 25 Jun 2024.

    Copyright: © 2024 Blevins, Honeycutt, Slattery, Goldberg, Rambousek, Tsui, Dodson, Shelton, Salemeh, Elfers, Chichura, Ashlaw, Zraika, Doyle and Roth. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: James E. Blevins, VA Puget Sound Health Care System, Veterans Health Administration, United States Department of Veterans Affairs, Seattle, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.