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

Authors: YANG, WANBAO - Texas A&M University; JIANG, WEN - Texas A&M University; LIAO, WANG - Texas A&M University; YAN, HUI - Texas A&M University; AI, WEIQI - Texas A&M University; PAN, QUAN - Texas A&M University; BRASHEAR, WESLEY - Texas A&M University; XU, YONG - Children'S Nutrition Research Center (CNRC); HE, LING - Johns Hopkins University School Of Medicine; GUO, SHAODONG - Texas A&M University

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/10/2024
Publication Date: 4/22/2024
Citation: Yang, W., Jiang, W., Liao, W., Yan, H., Ai, W., Pan, Q., Brashear, W.A., Xu, Y., He, L., Guo, S. 2024. An estrogen receptor a-derived peptide improves glucose homeostasis during obesity. Nature Communications. 15. Article 3410. https://doi.org/10.1038/s41467-024-47687-6.
DOI: https://doi.org/10.1038/s41467-024-47687-6

Interpretive Summary: Estrogen receptor a (ERa) is important for controlling blood sugar and energy balance in type 2 diabetes (T2DM), but how it works isn't fully clear. This study found that ERa can help regulate glucose even without its usual partner molecule. Mice without ERa in the liver struggled with blood sugar control, regardless of sex or whether they had their ovaries removed. ERa helps the liver use insulin more effectively by stopping the breakdown of a key protein called IRS1. A specific part of ERa (the 1-280 domain) is crucial for this effect. Researchers created a peptide based on this domain, which helped stabilize IRS1 and improve insulin sensitivity. Giving this peptide to obese mice greatly improved their blood sugar levels and fat profiles. This suggests that targeting this aspect of ERa could be a new way to treat T2DM, with the ERa-derived peptide showing potential as a treatment to improve insulin response.

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