{"doi":"10.1172/jci.insight.188414","title":"The cardiac METTL3/m6A pathway regulates the systemic response to Western diet","abstract":"Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves interorgan communication. The role of the heart in controlling systemic metabolic health is not clear. Adopting a mouse model of diet-induced obesity, we found that the landscape of N6-methyladenosine (m6A) on cardiac mRNA was altered following high-fat/high-carbohydrate feeding (Western diet). m6A is a critical posttranscriptional regulator of gene expression, the formation of which is catalyzed by methyltransferase-like 3 (METTL3). Through parallel unbiased approaches of Nanopore sequencing, mass spectrometry, and protein array, we found regulation of circulating factors under the control of METTL3. Mice with cardiomyocyte-specific deletion of METTL3 showed a systemic inability to respond to nutritional challenge, thereby mitigating the detrimental effects of Western diet. Conversely, increasing cardiac METTL3 level exacerbated diet-induced body weight gain, adiposity, and glucose intolerance. Our findings position the heart at the center of systemic metabolism regulation and highlight an m6A-dependent pathway to be exploited for the battle against obesity.","journal":"JCI Insight","year":2025,"id":528150,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":652418,"name":"Jacob Z. Longenecker","orcid":null,"position":1,"is_corresponding":false},{"id":1248030,"name":"Isabel S. Naarmann‐de Vries","orcid":"0000-0002-8115-5412","position":2,"is_corresponding":false},{"id":578381,"name":"Joan Serrano","orcid":"0000-0001-6002-116X","position":3,"is_corresponding":false},{"id":303899,"name":"Jennifer M. Petrosino","orcid":"0000-0002-5951-8942","position":4,"is_corresponding":false},{"id":578387,"name":"George A. Kyriazis","orcid":"0000-0001-9514-3482","position":5,"is_corresponding":false},{"id":17812,"name":"Christoph Dieterich","orcid":"0000-0001-9468-6311","position":6,"is_corresponding":false},{"id":303901,"name":"Federica Accornero","orcid":"0000-0003-1209-7228","position":7,"is_corresponding":false},{"id":537928,"name":"Charles P. Rabolli","orcid":"0000-0002-4383-8706","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:44.062153Z","pmid":"40272887","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":[]}