{"doi":"10.2337/db23-0180","title":"Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure","abstract":"Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-β1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-β1 deficiency decreased blood glucose levels in lean mice and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-β1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-β1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-β1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-β1→Foxo1→TGF-β1 looping by deleting TGF-β1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-β1→Foxo1→TGF-β1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS: Hepatic TGF-β1 levels are increased in obese humans and mice. Hepatic TGF-β1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-β1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-β1→Foxo1→TGF-β1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.","journal":"Diabetes","year":2023,"id":333934,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"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":695313,"name":"Weiqi Ai","orcid":"0000-0003-1386-8653","position":1,"is_corresponding":false},{"id":1061792,"name":"Yunmei Chen","orcid":"0000-0003-4656-8251","position":2,"is_corresponding":false},{"id":849197,"name":"Da Mi Kim","orcid":"0000-0001-9202-0276","position":3,"is_corresponding":false},{"id":695312,"name":"Zheng Shen","orcid":"0000-0002-0523-0767","position":4,"is_corresponding":false},{"id":695311,"name":"Wanbao Yang","orcid":"0000-0002-5519-8443","position":5,"is_corresponding":false},{"id":1024365,"name":"Wen Jiang","orcid":"0000-0003-0612-2917","position":6,"is_corresponding":false},{"id":484733,"name":"Yuxiang Sun","orcid":"0000-0002-6656-3733","position":7,"is_corresponding":false},{"id":260421,"name":"Stephen Safe","orcid":"0000-0002-2115-3060","position":8,"is_corresponding":false},{"id":695315,"name":"Shaodong Guo","orcid":"0000-0001-5126-731X","position":9,"is_corresponding":false},{"id":695314,"name":"Quan Pan","orcid":"0000-0001-8327-9657","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T01:09:44.297718Z","pmid":"37343276","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":[]}