An estrogen receptor α-derived peptide improves glucose homeostasis during obesity

Wanbao Yang, Wen Jiang, Wang Liao, Hui Yan, Weiqi Ai, Quan Pan, Wesley A. Brashear, Yong Xu, Ling He and Shaodong Guo ()
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Wanbao Yang: Texas A&M University
Wen Jiang: Texas A&M University
Wang Liao: Texas A&M University
Hui Yan: Texas A&M University
Weiqi Ai: Texas A&M University
Quan Pan: Texas A&M University
Wesley A. Brashear: Texas A&M University
Yong Xu: Baylor College of Medicine
Ling He: Johns Hopkins University School of Medicine
Shaodong Guo: Texas A&M University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Estrogen receptor α (ERα) plays a crucial role in regulating glucose and energy homeostasis during type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain incompletely understood. Here we find a ligand-independent effect of ERα on the regulation of glucose homeostasis. Deficiency of ERα in the liver impairs glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies reveal that ERα promotes hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediates the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we identify a peptide based on ERα 1-280 domain and find that ERα-derived peptide increases IRS1 stability and enhances insulin sensitivity. Importantly, administration of ERα-derived peptide into obese mice significantly improves glucose homeostasis and serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERα and indicate that ERα-derived peptide is a potential insulin sensitizer for the treatment of T2DM.

Date: 2024
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DOI: 10.1038/s41467-024-47687-6

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