Esculin ameliorates obesity-induced insulin resistance by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway

• Published in: Journal of ethnopharmacology 2024-01, Vol.319, p.117251-117251, Article 117251
• Main Authors: Yang, Yong-Yu, Qi, Jing-Jing, Jiang, Si-Yi, Ye, Ling
• Format: Article
• Language: English
• Subjects: Adipose tissue remodeling; Esculin; GLUT4; Insulin resistance; Obesity
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2023.117251

Cortex fraxini (also known as qinpi)—the bark of Fraxinus rhynchophylla Hance (Oleaceae)—is widely used as a Chinese traditional medicinal for its anti-inflammatory and anti-hyperuricemic activities. Obesity-induced insulin resistance (IR) is driving the rising incidence of type 2 diabetes mellitus and is related to pathological adipose tissue remodeling. Esculin, a major active component of Cortex fraxini, has anti-diabetic effects. However, whether esculin improves obesity-induced IR by regulating adipose tissue remodeling is unclear. The aims of the present study were to assess the effects of esculin on obesity-induced IR and to explore the underlying mechanisms. Obese IR C57BL/6J mice were treated with esculin (40 or 80 mg/kg/day) for 4 weeks. Oral glucose tolerance tests were used to assess insulin sensitivity. Histological analyses were performed to analyze the number and size distribution of adipocytes. Glucose uptake was assessed using 2-NBDG. Esculin had no effect on body weight gain but reduced fasting blood glucose, improved oral glucose tolerance, and increased insulin sensitivity. Esculin reduced adipocyte size and the expression levels of collagen 4A1 and tumor necrosis factor α and increased the number of adipocytes and the expression of vascular endothelial growth factor A. Esculin promoted the differentiation of 3T3-L1 cells and upregulated the mRNA expression of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ, activated the insulin receptor substrate 1 (IRS1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and enhanced the translocation of glucose transporter type 4 (GLUT4) and glucose uptake in adipocytes treated with palmitic acid. These data suggest that esculin increases insulin sensitivity by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway. [Display omitted] •Obesity-induced insulin resistance is the main cause of type 2 diabetes mellitus.•Esculin improves insulin sensitivity and adipose tissue remodeling in obese mice.•Esculin improves impaired glucose uptake by increasing GLUT4 translocation.•Esculin stimulates GLUT4 translocation via the IRS1/PI3K/AKT signaling pathway.•Our data indicate that esculin is a candidate for treatment of obesity-induced insulin resistance.