{"doi":"10.2337/db23-0571","title":"Leptin Reduction as a Required Component for Weight Loss","abstract":"Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss, and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.","journal":"Diabetes","year":2023,"id":325215,"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":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292390,"name":"Na Li","orcid":"0000-0002-0604-6312","position":1,"is_corresponding":false},{"id":833162,"name":"Wei Xiong","orcid":"0000-0003-2624-6474","position":2,"is_corresponding":false},{"id":1042726,"name":"Guannan Li","orcid":"0000-0002-6070-5008","position":3,"is_corresponding":false},{"id":281812,"name":"Sijia He","orcid":"0000-0003-3786-8770","position":4,"is_corresponding":false},{"id":282944,"name":"Zhuzhen Zhang","orcid":"0000-0001-6787-3920","position":5,"is_corresponding":false},{"id":282941,"name":"Qingzhang Zhu","orcid":"0000-0001-9382-8517","position":6,"is_corresponding":false},{"id":1042727,"name":"Nisi Jiang","orcid":"0000-0003-1837-7618","position":7,"is_corresponding":false},{"id":1043390,"name":"Christian Ikejiofor","orcid":null,"position":8,"is_corresponding":false},{"id":282946,"name":"Yi Zhu","orcid":"0000-0003-1650-1363","position":9,"is_corresponding":false},{"id":293726,"name":"May-Yun Wang","orcid":null,"position":10,"is_corresponding":false},{"id":877336,"name":"Xianlin Han","orcid":"0000-0003-4083-3640","position":11,"is_corresponding":false},{"id":1043391,"name":"Ningyang Zhang","orcid":null,"position":12,"is_corresponding":false},{"id":476976,"name":"Carolina Solis‐Herrera","orcid":"0000-0002-6215-9418","position":13,"is_corresponding":false},{"id":283831,"name":"Christine M. Kusminski","orcid":null,"position":14,"is_corresponding":false},{"id":105313,"name":"Zhiqiang An","orcid":"0000-0001-9309-2335","position":15,"is_corresponding":false},{"id":292392,"name":"Joel K. Elmquist","orcid":"0000-0001-6929-6370","position":16,"is_corresponding":false},{"id":275031,"name":"Philipp E. Scherer","orcid":"0000-0003-0680-3392","position":17,"is_corresponding":false},{"id":282945,"name":"Shangang Zhao","orcid":"0000-0002-9209-8206","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:08:22.919783Z","pmid":"37935033","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":[]}