2. Academic Validation
  3. A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss

A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss

  • Sci Rep. 2023 Jun 12;13(1):9554. doi: 10.1038/s41598-023-36178-1.
Kylie S Chichura # 1,  Clinton T Elfers # 2,  Therese S Salameh 2,  Varun Kamat 3,  Oleg G Chepurny 4,  Aelish McGivney 1,  Brandon T Milliken 1,  George G Holz 4 5,  Sarah V Applebey 6,  Matthew R Hayes 6,  Ian R Sweet 3,  Christian L Roth # 7 8,  Robert P Doyle # 9 10 11
Affiliations

Affiliations

  • 1 Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA.
  • 2 Seattle Children's Research Institute, 1900 Ninth Ave, Seattle, WA, 98101, USA.
  • 3 Diabetes Research Institute and Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, 98195, USA.
  • 4 Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
  • 5 Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA.
  • 6 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 7 Seattle Children's Research Institute, 1900 Ninth Ave, Seattle, WA, 98101, USA. Christian.roth@seattlechildrens.org.
  • 8 Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, 98105, USA. Christian.roth@seattlechildrens.org.
  • 9 Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA. Rpdoyle@syr.edu.
  • 10 Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA. Rpdoyle@syr.edu.
  • 11 Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA. Rpdoyle@syr.edu.
  • # Contributed equally.
PMID: 37308546 DOI: 10.1038/s41598-023-36178-1
Abstract

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of Insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

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