Abstract
AbstractThe estrogen receptor (ER) designated ERα has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
American Heart Association
Breast Cancer Research Foundation
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
U.S. Department of Health & Human Services | NIH | National Cancer Institute
U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference85 articles.
1. Hevener, A. L., Clegg, D. J. & Mauvais-Jarvis, F. Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. Mol. Cell Endocrinol. 418, 306–321 (2015).
2. Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).
3. Wagner, J. D. et al. Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with estradiol alone or combined with nomegestrol acetate. J. Clin. Endocrinol. Metab. 83, 896–901 (1998).
4. Kumagai, S., Holmang, A. & Bjorntorp, P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol. Scand. 149, 91–97 (1993).
5. Riant, E. et al. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 150, 2109–2117 (2009).
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献