{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:03:06Z","timestamp":1785499386416,"version":"3.56.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Obesity is a chronic, multifactorial disease that has reached epidemic status. The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is a key therapeutic target to achieve weight loss and glycemic control in obesity and type 2 diabetes mellitus. Tirzepatide and retatrutide, the latest generation of GLP-1-incorporating multi-agonists, target multiple receptors in complementary systems to achieve marked and sustained weight loss. However, the associated gastrointestinal (GI) side effects (\n                    <jats:italic>e.g.<\/jats:italic>\n                    , nausea, vomiting, diarrhea, abdominal pain) that often hinder patient compliance underscore a remaining need for therapies with better tolerability. GEP44, a novel, monomeric, chimeric peptide structurally based on native GLP-1, the GLP-1RA exendin-4 (Ex-4), and the gut-derived hormone peptide YY3-36 (PYY\n                    <jats:sub>3-36<\/jats:sub>\n                    ), is an agonist at the GLP-1R and multiple neuropeptide Y (NPY) receptors. This review summarizes the design rationale for GEP44 and preclinical evidence supporting its beneficial metabolic effects and tolerability. Like GLP-1, PYY\n                    <jats:sub>3\u201336<\/jats:sub>\n                    is associated with decreased food intake (FI), and co-administration of GLP-1RA and PYY\n                    <jats:sub>3\u201336<\/jats:sub>\n                    elicits synergistic food intake (FI)- and body weight (BW)-reducing effects with similar or enhanced blood glucose (BG)-lowering effects. Studies examining the efficacy of GEP44 to promote weight loss and improve glucoregulation in lean vs. diet-induced obese rodents report that peripheral administration generally decreases BW, FI, and insulin resistance and increases EE at equivalent or greater magnitudes than those observed with single GLP-1RAs in a GLP-1R-dependent manner with improved GI tolerability. These beneficial actions reflect GEP44\u2019s potential to expand the mechanistic scope of anti-obesity medications.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1925534","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:41:37Z","timestamp":1785498097000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Glucagon-like peptide-1 and peptide YY multi-agonism with GEP44 to optimize weight loss and glycemic control while reducing gastrointestinal side effects: the future of anti-obesity pharmacotherapy?"],"prefix":"10.3389","volume":"17","author":[{"given":"Melissa A.","family":"Burmeister","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler A.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]},{"name":"Department of Pharmacy Practice, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakeem J.","family":"Greer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]},{"name":"Department of Pharmacy Practice, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J.","family":"Hoggatt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, William Carey University School of Pharmacy","place":["Biloxi, MS, United States"]},{"name":"Department of Pharmacy 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