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

Estrogen improves insulin sensitivity and increases energy expenditure, contributing to sexual dimorphism regarding type 2 diabetes mellitus (T2DM) susceptibility. Estrogen receptor a (ERa) plays a crucial role in mediating estrogen action on glucose and energy homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we found a ligand-independent effect of ERa on the regulation of glucose homeostasis and identified an ERa-derived peptide as a potential insulin sensitizer. Deficiency of ERa but not ERß in the liver impaired glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies revealed that ERa promoted hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERa 1-280 domain mediated the ligand-independent effect of ERa on insulin sensitivity. Furthermore, we designed a peptide based on ERa 1-280 domain and found that ERa-derived peptide interacted with IRS1, increased IRS1 stability through suppressing its ubiquitination, and enhanced insulin sensitivity. Importantly, administration of ERa-derived peptide into obese mice significantly increased insulin sensitivity, attenuated glucose intolerance, and improved serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERa and indicate that ERa-derived peptide is a potential insulin sensitizer for the treatment of T2DM. Overall design: RNA-seq on the livers of db/db male mice treated with control and AF1 peptide