Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

Abstract

Ribas V, Nguyen MT, Henstridge DC, Nguyen A, Beaven SW, Watt MJ, Hevener AL. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ER␣-deficient mice. Am J Physiol Endocrinol Metab 298: E304 -E319, 2010. First published November 17, 2009 doi:10.1152/ajpendo.00504.2009.-Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)␣ leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ER␣-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPAR␣, PPAR␦, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ER␣ is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.estrogen receptor-␣; estrogen action; fatty acid metabolism; insulin action INSULIN RESISTANCE IS A CENTRAL FACTOR in the pathogenesis of type 2 diabetes and a defining feature of the metabolic syndrome, a constellation of abnormalities that includes obesity, hypertension, glucose intolerance, and dyslipidemia (21, 50). Prior to menopause, the incidence of type 2 diabetes is lower in women compared with men (50, 57). However, following menopause or ovariectomy this protection is lost, and a precipitous decline in insulin sensitivity coincides with increased fat mass and elevated circulating inflammatory markers [TNF␣, IL-6, and plasminogen activator inhibitor-1 (PAI-1)], LDL, triglycerides, and fatty acids (13,58,66). Similarly, alterations in estrogen receptor (ER) expression in both sexes have been linked with increased prevalence of certain aspects of the metabolic syndrome (22,(53)(54)67). We hypothesize that ER␣ is important in the regulation of tissue substrate metabolism and inflammatory signaling and thus is critical in modulating insulin action and adiposity.It is now widely accepted that impaired fatty acid metabolism and/or fatty acid oversupply cause heightened inflammatory signaling, and these are central contributors to whole body insulin resistance (3,41,84). Accumulation of lipid intermediates in insulin-responsive tissues can activate a host of "stress" kinases,...

Sex Differences in Obesity-Related Glucose Intolerance and Insulin Resistance

“…Impaired insulin sensitivity, glucose intolerance, and hyperinsulinemia in a man with a mutation of ER and thus lacking functional ER has been reported (180). Estrogen-dependent effects on glucose homeostasis through both ER and ER , whereas glucose tolerance is normal in ER -knockout mice (70,73,181,182). Additionally, ER deficiency increases fasting insulin levels, impairs glucose tolerance, and results in skeletal muscle insulin resistance (182), suggesting that ER may have a direct anti-diabetic role.…”

“…Estrogen-dependent effects on glucose homeostasis through both ER and ER , whereas glucose tolerance is normal in ER -knockout mice (70,73,181,182). Additionally, ER deficiency increases fasting insulin levels, impairs glucose tolerance, and results in skeletal muscle insulin resistance (182), suggesting that ER may have a direct anti-diabetic role. Insulin sensitivity is preserved in mice lacking ER although these animals become obese following a high-fat diet (183).…”

“…The development of ER and ER knockout mice (185) has demonstrated the participation of these receptors in the regulation of many processes related to glucose metabolism, including insulin sensitivity in the liver and muscle. Impaired insulin sensitivity and glucose tolerance as determined by the hyperinsulinemic clamp technique in ER deficient animals is attributed to either inadequate suppression of hepatic glucose production by insulin or impaired insulin action in skeletal muscle (181,182).Furthermore, insulin-stimulated glucose uptake in skeletal muscle, mediated by the glucose transporter isoform GLUT4, is suppressed in the absence of ER (181), however GLUT4 expression is not affected in mice lacking ER (186).…”

“…This inhibitory effect is absent in ER knockout animals (187), indicating that the protective effects of estrogens on inflammatory responses in the vessel wall are mediated by ER (187). In addition, adiponectin, an adipokine associated with suppression of insulin resistance and inflammation, is decreased in the absence of ER whereas plasminogen activator inhibitor-1, a surrogate marker of systemic inflammation is increased (182). Increased inflammation-associated changes following streptozotocininduced injury of pancreatic islets have been described in ER -deficient mice (Le May et al 2006).…”

“…Increased inflammation-associated changes following streptozotocininduced injury of pancreatic islets have been described in ER -deficient mice (Le May et al 2006). Moreover, enhanced inflammatory signaling and impaired fatty acid oxidation are found in the skeletal muscle of ER -knockout mice (182), further indicating an ER dependent regulation in inflammation which affects insulin resistance. In vitro studies have demonstrated 17 -estradiol-activated ER decreases the number of pro-inflammatory cytokines (161).…”