{"doi":"10.3389/fendo.2024.1432928","title":"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","abstract":"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.","journal":"Frontiers in Endocrinology","year":2024,"id":447146,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":265402,"name":"Mackenzie K. Honeycutt","orcid":null,"position":1,"is_corresponding":false},{"id":747628,"name":"Jared D. Slattery","orcid":null,"position":2,"is_corresponding":false},{"id":1265257,"name":"Matvey Goldberg","orcid":null,"position":3,"is_corresponding":false},{"id":1265258,"name":"June R. Rambousek","orcid":null,"position":4,"is_corresponding":false},{"id":1265259,"name":"Edison Tsui","orcid":null,"position":5,"is_corresponding":false},{"id":747625,"name":"Andrew D. Dodson","orcid":null,"position":6,"is_corresponding":false},{"id":1265260,"name":"Kyra A. Shelton","orcid":null,"position":7,"is_corresponding":false},{"id":1265261,"name":"Therese S. Salemeh","orcid":null,"position":8,"is_corresponding":false},{"id":701642,"name":"Clinton Elfers","orcid":"0000-0002-9400-8534","position":9,"is_corresponding":false},{"id":991561,"name":"Kylie S. Chichura","orcid":null,"position":10,"is_corresponding":false},{"id":1264770,"name":"Emily F. Ashlaw","orcid":"0009-0000-5920-2393","position":11,"is_corresponding":false},{"id":445351,"name":"Sakeneh Zraika","orcid":"0000-0003-4831-7034","position":12,"is_corresponding":false},{"id":240311,"name":"Robert P. Doyle","orcid":"0000-0001-6786-5656","position":13,"is_corresponding":false},{"id":311757,"name":"Christian L. Roth","orcid":"0000-0003-3037-4057","position":14,"is_corresponding":false},{"id":693567,"name":"James E. Blevins","orcid":"0000-0002-7587-0380","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:01:59.101070Z","pmid":"39104812","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}