{"doi":"10.1101/2024.03.04.583402","title":"Cell-state dependent regulation of PPAR <sub>γ</sub> signaling by ZBTB9 in adipocytes","abstract":"Abstract Adipocytes play a critical role in metabolic homeostasis. Peroxisome proliferator-activated receptor- γ (PPAR γ ) is a nuclear hormone receptor that is a master regulator of adipocyte differentiation and function. ZBTB9 was predicted to interact with PPAR γ based on large-scale protein interaction experiments. In addition, GWAS studies in the type 2 diabetes (T2D) Knowledge Portal revealed associations between Z btb9 and both BMI and T2D risk. Here we show that ZBTB9 positively regulates PPAR γ activity in mature adipocytes. Surprisingly Z btb9 knockdown (KD) also increased adipogenesis in 3T3-L1 cells and human preadipocytes. E2F activity was increased and E2F downstream target genes were upregulated in Zbtb9 -KD preadipocytes. Accordingly, RB phosphorylation, which regulates E2F activity, was enhanced in Zbtb9 -KD preadipocytes. Critically, an E2F1 inhibitor blocked the effects of Zbtb9 deficiency on adipogenic gene expression and lipid accumulation. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of Pparg expression via altered RB-E2F1 signaling. Our findings reveal complex cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipogenesis and adipocyte biology as both a positive and negative regulator of PPAR γ signaling depending on the cellular context, and thus may be important in the pathogenesis and treatment of obesity and T2D.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485976,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"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":429272,"name":"Alyssa Charrier","orcid":null,"position":1,"is_corresponding":false},{"id":1256421,"name":"Sunny Congrove","orcid":"0009-0005-5904-2322","position":2,"is_corresponding":false},{"id":428228,"name":"David A. Buchner","orcid":"0000-0003-3920-4871","position":3,"is_corresponding":false},{"id":428226,"name":"Xuan Xu","orcid":"0000-0001-5402-8410","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:07:57.049469Z","pmid":"38496622","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":[]}