An Estrogen Receptor α-Derived Peptide Improves Glucose Homeostasis During Obesity

Authors

Wanbao Yang
Wen Jiang
Wang Liao
Hui Yan
Weiqi Ai
Quan Pan
Wesley A Brashear
Yong Xu
Ling He
Shaodong Guo

Publication Date

4-22-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-47687-6

PMID

38649684

PMCID

PMC11035554

PubMedCentral® Posted Date

4-22-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Humans, Male, Mice, Diabetes Mellitus, Type 2, Estrogen Receptor alpha, Glucose, Homeostasis, Insulin Receptor Substrate Proteins, Insulin Resistance, Liver, Mice, Inbred C57BL, Mice, Knockout, Obesity, Ovariectomy, Peptides, Ubiquitination, Type 2 diabetes, Metabolic syndrome, Obesity

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.