How Estrogens Prevent From Lipid-Induced Insulin Resistance

Abstract

Premenopausal women have generally lower amounts of central adipose tissue and lower incidence of obesity-related metabolic abnormalities, which are frequently summarized as metabolic syndrome. Classical components of the metabolic syndrome are linked to impaired insulin action, also termed insulin resistance. Several mechanisms are currently discussed to underlie insulin resistance and comprise abnormal lipid metabolism with ectopic accumulation of triacylglycerols (TAGs), termed lipid overflow and lipotoxicity (1, 2), abnormal mitochondrial function (3), and oxidative stress as well as inflammation and endoplasmic reticulum stress (4). All these abnormalities can contribute to increased cardiovascular morbidity and mortality. Indeed, it is well known that premenopausal women exhibit a lower risk of cardiovascular mortality than ageand body-mass-index–matched men. This protective effect is lost in the postmenopausal state, when the circulating estrogen levels decline and women become more susceptible to obesity-associated insulin resistance. Decreasing estrogen production in female animal models by ovariectomy leading to a surgical menopause or by gene manipulation leading to down-regulation of estrogen synthesis has similar effects. These observations imply a relevant role of estrogens in the regulation of glucose metabolism and in the pathogenesis of insulin resistance. During the reproductive period, 17s-ethinyl-estradiol is the predominant estrogen and exerts its physiological actions through the two estrogen receptors (ERs), ER and ER . Although estrogen mainly acts via nuclear estrogen-responsive elements and recruitment of other coregulatory proteins to regulate gene transcription in all metabolically important tissues, there is also evidence for nongenomic effects via membrane-bound ER (reviewed in Ref. 5). Global ER deletion leads to increased body weight and insulin resistance, suggesting that this receptor is of critical importance for the metabolic estrogen action. In adipose tissue, 17s-ethinyl-estradiol was found to prevent fat (TAG) accumulation due to suppression of its target gene, lipoprotein lipase (LPL) an enzyme catalyzing lipogenesis. Aside from lower lipogenesis, 17s-ethinyl-estradiol increases expression of hormone-sensitive lipase (HSL), resulting in increased lipolysis, and stimulates lipid oxidation by increasing phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptorcoactivator 1 (PGC-1 ), and uncoupling protein 2 (UCP2) (5). In the liver, 17s-ethinyl-estradiol can reduce TAG accumulation, gluconeogenesis, and inflammatory pathways. Using ER inactivation showed that estrogens modulate functions of macrophages, of pancreatic s-cells to maintain insulin secretion via an antiapoptotic activity, and of hypothalamic neurons involved in energy homeostasis, maybe by regulating caloric intake and/or energy expenditure. In skeletal muscle, 17s-ethinyl-estradiol improves glucose disposal by modulating expression and the insulin-sensitive trafficking of glucose transporters [glucose transporter 4, (GLUT4)]. Finally, 17s-ethinyl-estradiol is thought to protect endothelial function and induce antiinflammatory effects in vascular tissue. Despite its multiplicity and complexity of effects, the exact molecular mechanisms linking 17s-ethinyl-estradiol with improved insulin signaling and whole-body glucose and lipid disposal have not yet been resolved.