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Publication
Transcriptomic and epigenomic signatures of liver metabolism and insulin
sensitivity in aging mice.
Authors González JT, Scharfman OH, Zhu W, Kasamoto J, Gould V, Perry RJ, Higgins-Chen AT
Submitted By Submitted Externally on 7/7/2025
Status Published
Journal Mechanisms of ageing and development
Year 2025
Date Published 6/1/2025
Volume : Pages 225 : 112068
PubMed Reference 40324540
Abstract Age-related declines in insulin sensitivity and glucose metabolism contribute to
metabolic disease. Despite the liver's central role in glucose homeostasis, a
comprehensive phenotypic characterization and concurrent molecular analysis of
insulin resistance and metabolic dysfunction in the aging liver is lacking. We
characterized hepatic insulin resistance and mitochondrial metabolic defects
through metabolic cage, hyperinsulinemic-euglycemic clamp, and tracer studies
paired with transcriptomic and DNA methylation analyses in young and aged male
mice. Aged mice exhibited benchmark measures of whole body and liver insulin
resistance. Aged mice showed lower pyruvate dehydrogenase flux, decreased fatty
acid oxidation and citrate synthase fluxes, and increased pyruvate carboxylase
flux under insulin-stimulated conditions. Molecular analysis revealed
age-related changes in metabolic genes Pck1, Socs3, Tbc1d4, and Enpp1.
Unsupervised network analysis identified an intercorrelated phenotype module
(ME-Glucose), RNA module, and DNA methylation module. The DNA methylation module
was enriched for lipid metabolism pathways and TCF-1 binding, while the RNA
module was enriched for MZF-1 binding and regulation by miR-155-5p.
Protein-protein interaction network analysis revealed interactions between
module genes and canonical metabolic pathways, highlighting genes including
Ets1, Ppp1r3b, and Enpp3. This study reveals novel genes underlying age-related
hepatic insulin resistance as potential targets for metabolic interventions to
promote healthy aging.




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