Abstract
Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of β-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERβ-ERE luc expression system with greater response through ERβ in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERβ through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.
Highlights
Type 2 diabetes mellitus is a chronic metabolic disorder associated with impaired glucose and lipid metabolism
ERβ predominates, whereas, in adipose tissue, ERα is the predominating isoform [7]. Estrogens exert their biological action via nuclear Estrogen receptors (ERs), which directly bind to specific estrogen responsive elements (EREs) in the promoter region of target genes [3]
To identify the estrogenic potential, BSD was assayed on estrogen receptor α and estrogen receptor β dependent activity in HEK-293T cells transiently transfected with plasmids containing either ERα or ERβ and an estrogen-responsive element (ERE)-fused luciferase reporter plasmid (ERα/β-ERE luc)
Summary
Type 2 diabetes mellitus is a chronic metabolic disorder associated with impaired glucose and lipid metabolism. Estrogens are known to modulate fat distribution and metabolism, and insulin sensitivity In support of this notion, mice deficient in estrogen receptor gene display features of metabolic syndrome such as increased adiposity, glucose intolerance, and insulin resistance [2], demonstrating the implication of estrogens in nutrient metabolism. Estrogens exert their biological effects through binding to their receptors which exist in two isoforms, ERα and ERβ. ER deficient mice displayed altered GLUT4 expression and glycemic homeostasis [5] and selective ERβ activation stimulates skeletal muscle growth and regeneration [15] Overall, it seems that estrogens via extra nuclear mechanisms might regulate glucose homeostasis in insulin-sensitive metabolic tissues
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