An estrogen receptor -derived peptide improves glucose homeostasis during obesity.
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Estrogen receptor (ER) 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 ER on the regulation of glucose homeostasis. Deficiency of ER in the liver impairs glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies reveal that ER promotes hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ER 1-280 domain mediates the ligand-independent effect of ER on insulin sensitivity. Furthermore, we identify a peptide based on ER 1-280 domain and find that ER-derived peptide increases IRS1 stability and enhances insulin sensitivity. Importantly, administration of ER-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 ER and indicate that ER-derived peptide is a potential insulin sensitizer for the treatment of T2DM.
