In vivo stimulation of oestrogen receptor α increases insulin‐stimulated skeletal muscle glucose uptake

Abstract

Previous studies suggest oestrogen receptor α (ERα) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERα modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERα activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg⁻¹), oestradiol benzoate (EB; 20 μg kg⁻¹), the ERβ agonist diarylpropionitrile (DPN, 10 mg kg⁻¹) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting.Activation of ERα with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL)muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ERα positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ERα stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.