The 17-Beta-Estradiol Improves Insulin Sensitivity in a Rapid Estrogen Receptor Alpha-Dependent Manner in an Animal Model of Malnourishment

Marta Garcia-Arevalo, Estela Lorza-Gil, Nayara Leite, Sergio Brunetto, Antonio Carlos Boschero, Everardo Magalhaes Carneiro


Background: Protein restriction causes metabolic programming to maintain glucose homeostasis in rodents. They develop increased insulin sensitivity in peripheral tissues and reduced insulin secretion by pancreatic beta cells. Estradiol (E2) is a steroid hormone involved in the control of energy balance and glucose homeostasis. Here, we assessed the role of estrogen receptors (ERs) on glucose homeostasis in malnourished mice and the effect of E2 on insulin signaling.

Methods: Post-weaned Swiss male mice were fed a low-protein (LP, 6%) or chow diet (control, 14%) for 8 weeks. The malnourished phenotype in LP mice was confirmed by different physiological parameters. Hypersensitivity to insulin was demonstrated by a higher glucose infusion in the LP group compared with the control by euglycemic-hyperinsulinemic clamp.

Results: The administration of 10 g/kg E2 during the clamp induced a significant increase in the glucose infusion rate in the LP group compared with the control, indicating enhanced insulin sensitivity in LP mice. In addition, E2 administration increased glucose uptake by peripheral tissues. These effects were blunted in mice treated with general ER antagonists (ICI 182,780 and MPP). However, PHTTP failed to interfere with the E2 effect on insulin sensitivity. In the estradiol LP-treated mice, the activity of the insulin pathway was augmented, as demonstrated by higher AKT phosphorylation and glucose uptake by the skeletal muscle.

Conclusion: Thus, we show an acute effect of E2 on insulin signaling in the skeletal muscle of protein-restricted mice. It is mediated by ERalpha, which interacts directly with phosphatidylinositol 3-kinase (PI3K), increasing the phosphorylation of AKT and consequently, glucose uptake in muscle.

J Endocrinol Metab. 2019;9(5):133-146


Insulin sensitivity; Estradiol; Estrogen receptor alpha; Low protein diet; Malnourishment

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