The diversity of sex steroid action: regulation of metabolism by estrogen signaling

Abstract

The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic b cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Although roles for the classic ERs are well documented in these conditions (Faulds et al, 2012), GPER knockout mice also exhibit insulin resistance, glucose intolerance, dyslipidemia, obesity, and an elevation of proinflammatory cytokines with reduced adiponectin levels (Martensson et al, 2009;Sharma et al, 2013;Davis et al, 2014), despite displaying no differences in food intake or locomotor activity (Sharma et al, 2013;Davis et al, 2014). G-1, like E2, stimulates insulin secretion from the islets of mice (Sharma and Prossnitz, 2011) and humans (Kumar et al, 2011), with both G-1-and E2-mediated insulin secretion absent in islets of GPER knockout mice (Sharma and Prossnitz, 2011).…”

Sex Differences in the Metabolic Syndrome: Implications for Cardiovascular Health in Women

“…E 2 secretion and action is now implicated in a variety of processes involved in adipocyte biology and glucose and lipid metabolism. Several excellent reviews on the topic have recently been published (38,39 ), with the balance of data supporting several critical metabolic functions including (a) anorexigenic action via central nervous system control of feeding behavior, (b) augmented glucose disposal in skeletal muscle via actions on several proteins in the insulin signaling pathway and by increased glucose transporter type 4 translocation, (c) prevention of visceral fat accumulation and decreased lipogenic activity of lipoprotein lipase in adipose tissue, and (d) antiapoptotic effects on pancreatic ␤-cells. In some tissues, such as adipose tissue, ER␣ and ER␤ appear to have opposing actions, for instance ER␣ agonism decreases adipocyte proliferation and hypertrophy, whereas ER␤ promotes adipose tissue expansion.…”

Estrogens in the Control of Growth Hormone Actions in Liver

“…E2 can modulate GH actions on liver by acting centrally, by regulating GH secretion, and peripherally, modulating GH responsiveness. Importantly, the liver expresses ER which regulates development (Fisher et al, 1984), hepatic metabolic pathways (D'Eon et al, 2005;Ribas et al, 2010;Faulds et al, 2011), body growth (Vidal et al, 2000), protection from drug-induced toxicity (Yamamoto et al, 2006), hepatocarcinogenesis (Yager et al, 1994;Bigsby and Caperell-Grant, 2011), fertility (Della Torre et al, 2011), as well as lipid metabolism and insulin sensitivity (Simpson et al, 2005;Foryst-Ludwig and Kintscher, 2010).Thus, the liver is a sex steroid responsive organ and represents a site where critical interactions between estrogens and GH could be developed.…”

“…5.4 E2 is a critical regulator of lipid metabolism and insulin sensitivity: Potential crosstalk with GH Estrogens, acting on both ER and ERare recognized as important regulators of glucose homeostasis and lipid metabolism (Simpson et al, 2005;Faulds et al, 2011). Both male and female ERKO mice develop insulin resistance and impaired glucose tolerance, similar to humans lacking ER or aromatase.…”

“…Particularly, E2 has been shown to induce Suppressor of Cytokine Signalling (SOCS)-2, a protein inhibitor for cytokine signalling, which in turn negatively regulate GHRJanus Kinase (JAK)-2-STAT5 pathway (Leung et al, 2004). Finally, the liver is a direct target of estrogens because it expresses ER (Heldring et al, 2007) which is connected with liver development (Fisher et al, 1984), regulation of hepatic metabolic pathways (D'Eon et al, 2005;Ribas et al, 2010;Faulds et al, 2011), growth (Vidal et al, 2000), protection from druginduced toxicity (Yamamoto et al, 2006), hepatocarcinogenesis (Bigsby and Caperell-Grant, 2011), fertility (Della Torre et al, 2011), as well as lipid metabolism and insulin sensitivity (Simpson et al, 2005;Foryst-Ludwig and Kintscher, 2010). Therefore, estrogen-GH interactions are relevant because physiological roles these hormones have in mammals, and the widespread use of estrogen and estrogen-related compounds in human.…”