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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Community Health and Preventive Medicine Commons, Dietetics and Clinical Nutrition Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Neurosciences Commons, Nutrition Commons