Single-cell and spatial omics in liver identify cell-cell communication regulators in aging and insulin resistance

The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin resistance during aging remains to be elucidated. Using single-cell RNA-seq, ATAC-seq, and spatial transcriptomics, we studied liver cellular composition and zonation in young, insulin-sensitive mice and old mice with varying degrees of insulin resistance. Aging reduced pericentral zone 3 hepatocyte population but increased mid-zone 2 hepatocytes and hepatic stellate cells (HSCs). The interaction of aging and insulin resistance led to further zone 3 contraction and zone 2 expansion. Cell-cell communication and spatial proximity analysis revealed reduced hepatocyte growth factor (HGF) signaling activity from HSCs to zone 3 hepatocytes in aging and insulin resistance. In HGF activator (HGFAC)-knockout mice, a significant reduction in the zone 3 hepatocyte proportion was observed. Treating insulin-resistant aged mice with HGF reversed zone 3 contraction and improved insulin sensitivity. These findings highlight the significance of liver zonation dynamics in aging-associated insulin resistance.