{"doi":"10.1101/2022.11.07.515236","title":"GDF3 is an obesity-induced regulator of TGFβ superfamily signaling","abstract":"ABSTRACT Growth differentiation factor 3 (GDF3) is a relatively understudied member of the TGFβ superfamily that is highly expressed during development. However, the function of GDF3 in adult biology is contentious. We use in vivo approaches to show that GDF3 loss-of-function in adipose tissue of obese adult mice causes reduced body weight and improved whole-body insulin sensitivity. These effects are accompanied by altered regulation of genes targeted by the TGFβ superfamily in vivo . Using in vitro approaches, we show that GDF3 can influence both arms of the TGFβ superfamily: GDF3 simultaneously inhibits BMP signaling and activates activin-like SMAD 2/3 signaling. We identify the type II receptors mediating this activity. GDF3 binds to the type II receptors BMPR2, ACTRIIA and ACTRIIB and achieves dose-dependent inhibition of multiple BMP proteins including BMP2, BMP7, BMP9, BMP10, and BMP15 in vitro . We also find that GDF3 activates TGFβ/activin-like SMAD2/3 signaling. Unbiased expression profiling confirms that GDF3 both attenuates BMP2-regulated gene expression and drives TGFβ/activin-like gene expression. Together these results provide much needed clarity to both the molecular pathways involved in GDF3 signaling and the physiological effects of GDF3 loss of function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300593,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991141,"name":"Nagasuryaprasad Kotikalapudi","orcid":"0000-0003-2126-9052","position":1,"is_corresponding":false},{"id":307850,"name":"Gregory R. Gipson","orcid":"0000-0002-3698-4182","position":2,"is_corresponding":false},{"id":241051,"name":"Luca Troncone","orcid":"0000-0002-2056-8758","position":3,"is_corresponding":false},{"id":991142,"name":"Kylie Vestal","orcid":"0000-0001-6421-8488","position":4,"is_corresponding":false},{"id":255162,"name":"David E. Maridas","orcid":"0000-0001-6680-6005","position":5,"is_corresponding":false},{"id":31462,"name":"Anton Gulko","orcid":"0000-0003-3471-9665","position":6,"is_corresponding":false},{"id":284998,"name":"Linus Tsai","orcid":"0000-0002-0134-6949","position":7,"is_corresponding":false},{"id":255163,"name":"Vicki Rosen","orcid":"0000-0002-4029-1055","position":8,"is_corresponding":false},{"id":241058,"name":"Paul B. Yu","orcid":"0000-0003-2145-4944","position":9,"is_corresponding":false},{"id":307855,"name":"Thomas B. Thompson","orcid":"0000-0002-7041-5047","position":10,"is_corresponding":false},{"id":23889,"name":"Alexander S. Banks","orcid":"0000-0003-1787-6925","position":11,"is_corresponding":false},{"id":284987,"name":"Deepti Ramachandran","orcid":"0000-0003-1113-1295","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T00:31:53.559757Z","pmid":null,"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":[]}