Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, 77843, USA.
High Performance Research Computing, Texas A&M University, College Station, TX, USA.
Nat Commun. 2024 Apr 22;15(1):3410. doi: 10.1038/s41467-024-47687-6.
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.
雌激素受体 α（ERα）在 2 型糖尿病（T2DM）期间调节葡萄糖和能量稳态中发挥着关键作用。然而，其潜在机制仍不完全清楚。在这里，我们发现 ERα 对葡萄糖稳态调节具有配体非依赖性效应。肝脏中 ERα 的缺失会损害雄性、雌性和去卵巢（OVX）雌性小鼠的葡萄糖稳态。机制研究表明，ERα 通过抑制泛素化诱导的 IRS1 降解来促进肝胰岛素敏感性。ERα 的 1-280 结构域介导 ERα 对胰岛素敏感性的配体非依赖性效应。此外，我们鉴定出一种基于 ERα 1-280 结构域的肽，并发现 ERα 衍生肽增加 IRS1 的稳定性并增强胰岛素敏感性。重要的是，将 ERα 衍生肽施用于肥胖小鼠可显著改善葡萄糖稳态和血清脂质谱。这些发现为通过靶向 ERα 的配体非依赖性效应治疗 T2DM 开辟了道路，并表明 ERα 衍生肽是治疗 T2DM 的潜在胰岛素增敏剂。
