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

Wei Zhao; Xinfeng Jiao; Kang Du; Qiushi Sun; Junyan Duan; Yang Cao; Xiyu Shen; Zaid Said; Satya S Karri; Peter Ellsworth; Wenjing Hu; Ashot Sargsyan; Inna Astapova; So Yeon Kim; John Gonzalez; Albert T Higgins-Chen; Rachel J Perry; Ekihiro Seki; Mark A Herman; Bogi Andersen; Qing Nie; Qin Yang

doi:10.1016/j.metabol.2026.156630

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

Metabolism. 2026 Aug:181:156630. doi: 10.1016/j.metabol.2026.156630. Epub 2026 May 9.

Authors

Wei Zhao¹, Xinfeng Jiao², Kang Du², Qiushi Sun², Junyan Duan³, Yang Cao², Xiyu Shen², Zaid Said², Satya S Karri³, Peter Ellsworth², Wenjing Hu², Ashot Sargsyan⁴, Inna Astapova⁵, So Yeon Kim⁶, John Gonzalez⁷, Albert T Higgins-Chen⁸, Rachel J Perry⁹, Ekihiro Seki⁶, Mark A Herman⁵, Bogi Andersen³, Qing Nie¹⁰, Qin Yang¹¹

Affiliations

¹ Department of Mathematics and the NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA; Diabetes Center, University of California Irvine, Irvine, CA, USA.
² Diabetes Center, University of California Irvine, Irvine, CA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
³ Diabetes Center, University of California Irvine, Irvine, CA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
⁴ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
⁵ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
⁶ Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁷ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
⁸ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
⁹ Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.
¹⁰ Department of Mathematics and the NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA; Diabetes Center, University of California Irvine, Irvine, CA, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA. Electronic address: qnie@uci.edu.
¹¹ Diabetes Center, University of California Irvine, Irvine, CA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. Electronic address: qin.yang@uci.edu.

Abstract

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.

Keywords: Aging; Cell-cell communication; Insulin resistance; Liver zonation; Single-cell analysis.

MeSH terms

Aging* / genetics
Aging* / metabolism
Aging* / physiology
Animals
Cell Communication* / genetics
Cell Communication* / physiology
Hepatic Stellate Cells / metabolism
Hepatocyte Growth Factor / metabolism
Hepatocytes / metabolism
Insulin Resistance* / genetics
Insulin Resistance* / physiology
Liver* / cytology
Liver* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Single-Cell Analysis
Single-Cell Gene Expression Analysis
Spatial Transcriptomics

Substances

Hepatocyte Growth Factor

Abstract

MeSH terms

Substances

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