Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue

Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ER alpha and ER beta in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab 297: E124-E133, 2009. First published April 14, 2009; doi: 10.1152/ajpendo.00189.2009.-Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT) 4 is reduced by estrogen receptor (ER)beta agonists. In the present study, to investigate the relative contributions of ER alpha and ER beta in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER-/- mice. ER beta(-/-) mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ER beta(-/-) mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ER beta(-/-) mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ER beta antagonist in SM but had no effect on WAT. In ER beta(-/-) mice, Tam did not affect GLUT4 in SM but acted as an ER beta antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ER alpha and ER beta, ER beta-mediated repression of GLUT4 predominates in SM but ER alpha-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ER alpha predominates in WAT and ER beta in SM.