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
  • 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. [email protected].
  • 8. Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, 98105, USA. [email protected].
  • 9. Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA. [email protected].
  • 10. Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA. [email protected].
  • 11. Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA. [email protected].
  • # 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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