FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survivalOA
Actin-bundling protein Fascin1(FSCN1)is encoded by the Fscn1 gene and is crucial for cytoskeletal remodeling and cellular migration.Although a previous study linked Fscn1 deficiency to neonatal lethality in mice,the underlying metabolic mechanism remains unclear.In this study,we report that systemic knockout(KO)of Fscn1 leads to 52.2%mortality within 24 h post-birth,accompanied by severe hypoglycemia in KO pups compared with their littermates.Remarkably,this lethality is fully rescued by oral glucose administration,indicating a glucose supply-dependent survival mechanism.Surviving Fscn1-KO neonates display persistent developmental deficits,including growth retardation and depleted lipid stores,despite intact canonical insulin-regulated hepatic gluconeogenic pathways.Transcriptomic profiling of P0 livers reveals that Fscn1 loss predominantly disrupts metabolic pathways,with the glycerol phosphate shuttle being the most significantly downregulated module.Mechanistically,Fscn1-KO livers exhibit markedly reduced protein levels of glycerol-3-phosphate dehydrogenase isoforms(GPD1/GPD2),key enzymes bridging glycolysis and gluconeogenesis.Consistently,glycerol tolerance tests demonstrate impaired glycerol-to-glucose conversion in Fscn1-KO mice,confirming defective glycerol-driven gluconeogenesis.Our findings establish FSCN1 as a novel cytoskeletal-metabolic integrator essential for neonatal survival by sustaining hepatic glucose production from glycerol,thus revealing an unexpected role of actin dynamics in coordinating metabolic adaptation during early postnatal development.
Xiangxiang Liu;Yuanzhao Hu;Liangwei Wu;Yiwen Zhang;Lei Sang;Yake Gao;Lei He;Wenyong Xiong;Shengyu Yang;Jianwei Sun
Yunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,ChinaKey Laboratory of Medicinal Chemistry for Natural Resource,Ministry of Education,Yunnan Key Laboratory of Research and Development for Natural Products,School of Pharmacy,Yunnan University,Kunming 650500,ChinaDepartment of Cell and Biological System,Penn State Cancer Institute,Penn State College of Medicine,Hershey,PA 17033,USAYunnan Key Laboratory of Cell Metabolism and Diseases,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650500,China
医药卫生
FSCN1neonatal mice survivalhypoglycemiagluconeogenesis
《Acta Biochimica et Biophysica Sinica》 2026 (3)
P.584-594,11
supported by the grants from the National Natural Science Foundation of China(NSFC)fund(Nos.82273460,32260167)the Yunnan Fundamental Research Projects(No.202401AS070133)grants(Nos.2024Y014,S202410673217)from Yunnan University.
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