{"doi":"10.1101/2025.11.18.689117","title":"<i>De Novo</i> Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis","abstract":"Abstract Fasting blood uridine is increased in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis to the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and diet-induced obesity, while suppression of hepatic pyrimidine synthesis promotes obesity and insulin resistance. The metabolic sequalae of hepatic pyrimidine synthesis suppression, however, is not associated with altered plasma uridine concentration. Instead, it is associated with an increased hepatic glucose production and a decreased hepatic insulin clearance, two key functions of hepatocytes in regulating systemic energy homeostasis. We found that enhanced gluconeogenesis is the primary reason for increased hepatic glucose production. Moreover, uridine, which was maintained stable in the circulation by adipose tissue and the liver, preferentially shut down pyrimidine synthesis in hepatocytes but not adipocytes at blood concentrations that occur with fasting. Remarkably, uridine, at fasting levels, increases gluconeogenesis further in hepatocytes when de novo pyrimidine synthesis is suppressed, indicating a synergistical action of uridine and its biosynthesis pathway in promoting hepatic glucose production, a mechanism highly relevant to the pathophysiology of insulin resistance in obesity. Theologically, maintenance of blood uridine within the narrow range protects mammals from high-rate spontaneous tumorigenesis. Since obesity promotes an increase in blood uridine from adipocytes, suppressing uridine synthesis in hepatocytes becomes a critical response to lower spontaneous tumorigenesis. Pyrimidine synthesis suppression in hepatocytes, however, promotes gluconeogenesis and ultimately triggers obesity and T2D. These findings suggest a new paradigm for the etiology of metabolic deterioration in diet-induced obesity, in which perturbations in uridine promotes obesity and T2D.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":582768,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"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":1495116,"name":"Pradnya H. 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Fueger","orcid":"0000-0003-0602-6458","position":10,"is_corresponding":false},{"id":673941,"name":"Lihua Jin","orcid":"0000-0002-2685-6048","position":11,"is_corresponding":false},{"id":848200,"name":"Wendong Huang","orcid":"0000-0003-3735-9466","position":12,"is_corresponding":false},{"id":235977,"name":"Philip L. Lorenzi","orcid":"0000-0003-0385-7774","position":13,"is_corresponding":false},{"id":270244,"name":"Lin Tan","orcid":"0000-0002-9400-1754","position":14,"is_corresponding":false},{"id":434048,"name":"Markus Kalkum","orcid":"0000-0002-9506-671X","position":15,"is_corresponding":false},{"id":275031,"name":"Philipp E. Scherer","orcid":"0000-0003-0680-3392","position":16,"is_corresponding":false},{"id":282531,"name":"Zhao V. 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