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

Abstract

Non-technical summary Previous studies show that oestrogen is beneficial for maintaining blood glucose levels and helping the body respond to insulin. Despite these previous findings, the mechanism by which oestrogen acts is unknown. We show that specific activation of oestrogen receptor α (ERα) increases glucose uptake into skeletal muscle when insulin is present. Activation of oestrogen receptor β (ERβ) alone or activation of both ERα and ERβ together did not increase glucose uptake into skeletal muscle. This suggests that oestrogen's beneficial effect occurs by activating ERα. These results have important implications for understanding the mechanisms of glucose homeostasis, particularly in postmenopausal women with low oestrogen levels.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.

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

“…E 2 exerts an anti-atherogenic effect influencing lipolysis and lipogenesis thus reducing the concentration of lipids in both the blood (Shi et al 2013) and tissues (Hewitt et al 2004, Jelenik, Roden 2013. Moreover, E 2 might decrease synthesis and increase FFA oxidation during hyperinsulinemia (Musatov et al 2007, Gorres et al 2011). …”

“…E 2 exerts beneficial effects on the cardiovascular system by reducing nuclear factor kappa-B (NFkB), IkB and iNOS expression during ischemia (Karpuzoglu, Ahmed 2006). Under normal conditions, E 2 also influences energy usage by regulating GLUT and CD36 in heart (Gorres et al 2011, Tepavcevic et al 2011.…”

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

“…41 Other possibilities include increased ERa expression after TBI 32 and an increase in the neurological score by lowering intracranial pressure. 28,41 Furthermore, the increase in progesterone and progesterone receptor levels 16 may mimic the effects of PPT and estrogen on VCS score. This increase in progesterone and progesterone receptor levels may be sufficient to mimic the effects of PPT and estrogen on VCS score.…”

Estrogen and n-3 polyunsaturated fatty acid supplementation have a synergistic hypotriglyceridemic effect in ovariectomized rats

“…Previous studies showed that an ovariectomy procedure in rats caused hypertriglyceridemia (Hassan et al 2013) and, in a human study, circulating TG concentrations were higher in postmenopausal than pre-menopausal women (Furusyo et al 2013). Additionally, an estrogen injection prevented TG accumulation in liver and muscle of ovariectomized (OVX) mice by reducing fatty acid synthesis, increasing b-oxidation by down-regulating ACC1 and FAS, and up-regulating AMPK (D'Eon et al 2005;Gorres et al 2011). However, the effects of E 2 are unknown in regard to hepatic TG synthesis.…”