Estrogen Receptors in Glucose Homeostasis

Metabolic diseases affect more than 230 million people worldwide with an expectancy to increase to around 350 million in the coming 25 years. It is currently the fourth leading cause of death by disease. The metabolic syndrome refers to a group of interrelated metabolic abnormalities that include disturbed glucose homeostasis, insulin resistance (IR), increased body weight and abdominal fat accumulation, mild dyslipidemia and hypertension. Individuals with the metabolic syndrome have an increased risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D). Estrogens have traditionally been connected with female reproduction, however, the importance of these hormones in tissues outside of the reproductive system including the liver, bone, the cardiovascular system and brain have since been established (Gruber et al., 2002). Estrogen and the estrogen receptors (ERs) are well-known regulators of glucose homeostasis and several epidemiological and prospective studies associate estrogen to various aspects of the metabolic syndrome (Louet et al., 2004). Postmenopausal women develop visceral obesity, IR and are at high risk for T2D. Treatment of healthy postmenopausal women with estrogen has been shown to improve insulin sensitivity and to lower blood glucose (Crespo et al., 2002). Furthermore, hormone replacement therapy (HRT) in postmenopausal women with coronary artery disease was associated with a 35% reduction in the incidence of T2D (Kanaya et al., 2003). Male aromatase-deficient patients, as well as a male patient with loss of ER┙ function, display impaired glucose metabolism, IR and hyperinsulinemia (Zirilli, et al. 2008). In addition, the aromatase deficient patients showed impaired liver functions, hepatic steatosis, and altered lipid profile (Maffei, et al. 2004). Additional observations in rodents support the notion that estrogen mediates antidiabetic effects. For example, female rodents are protected against hyperglycemia, unless they are ovariectomized, in spontaneous rodent models of T2D. Studies in knock-out mouse models have shed light on the role of estrogen and its receptors in rodent obesity and glucose tolerance. Mice with functional knock-out of the aromatase enzyme (ArKO mice) are unable to synthesize endogenous estrogen and display an obese and insulin resistant phenotype (Fisher et al., 1998). A similar phenotype was observed in mice lacking ER┙ (ER┙KO) but not in mice lacking ER┚ (ER┚KO), indicating that ER┙ is the major mediator for the estrogenic effects on insulin sensitivity and body weight (Heine et