Long-Term Administration of Estradiol Decreases Expression of Hepatic Lipogenic Genes and Improves Insulin Sensitivity in ob/ob Mice: A Possible Mechanism Is through Direct Regulation of Signal Transducer and Activator of Transcription 3 (original) (raw)
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Endocrinology, 2013
Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM...
Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity
Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. development of insulin resistance in the liver is a key event that drives dyslipidemia and predicts diabetes and cardiovascular risk with obesity. Clinical data show that estrogen signaling in males helps prevent adiposity and insulin resistance, which may be mediated through estrogen receptor-␣ (ER␣). The tissues and pathways that mediate the benefits of estrogen signaling in males with obesity are not well defined. In female mice, ER␣ signaling in the liver helps to correct pathway-selective insulin resistance with estrogen treatment after ovariectomy. We assessed the importance of liver estrogen signaling in males using liver ER␣-knockout (LKO) mice fed a high-fat diet (HFD). We found that the LKO male mice had decreased insulin sensitivity compared with their wild-type floxed (fl/fl) littermates during hyperinsulinemic euglycemic clamps. Insulin failed to suppress endogenous glucose production in LKO mice, indicating liver insulin resistance. Insulin promoted glucose disappearance in LKO and fl/fl mice similarly. In the liver, insulin failed to induce phosphorylation of Akt-Ser 473 and exclude FOXO1 from the nucleus in LKO mice, a pathway important for liver glucose and lipid metabolism. Liver triglycerides and diacylglycerides were also increased in LKO mice, which corresponded with dysregulation of insulin-stimulated ACC phosphorylation and DGAT1/2 protein levels. Our studies demonstrate that estrogen signaling through ER␣ in the liver helps prevent whole body and hepatic insulin resistance associated with HFD feeding in males. Augmenting hepatic estrogen signaling through ER␣ may lessen the impact of obesity on diabetes and cardiovascular risk in males.
Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action
PLoS ONE, 2013
An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERa) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERa recapitulates metabolic phenotypes of ERKO mice we generated a liverselective ERaKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERa selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERa action may not be the responsible factor for the previously identified hepatic insulin resistance in ERaKO mice. Citation: Matic M, Bryzgalova G, Gao H, Antonson P, Humire P, et al. (2013) Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action. PLoS ONE 8(2): e57458.
Antidiabetic actions of estrogen: Insight from human and genetic mouse models
Current Atherosclerosis Reports, 2004
There is increasing evidence both in humans and rodents linking the endogenous estrogen 17β-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic β-cell function/survival and insulin secretion in conditions of oxidative stress.
American Journal of Physiology-Endocrinology and Metabolism, 2008
The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17β-estradiol (E2) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E2, given daily (50 μg/kg sc) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E2treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression l...
The Mediation of Hepatic Lipogenesis Through Estrogens
Estrogens have been shown to protect against various diseases and disastrous metabolic consequences of poor diets. Although a large body of research demonstrates estrogen's ability to control food intake, adipogenesis, and oxidative stress, research regarding the effects of estrogens on hepatic lipogenesis, steatosis, and non-alcoholic fatty liver disease is only now accumulating. Estrogen deficiency in both human and rodent models directly results in the upregulation of hepatic lipogenic signaling -in both serum and hepatic triglyceride contentwhich leads to the development of fatty liver. In all models, estrogen replacement completely reverses these outcomes. Similar to the endogenous estrogen hormone, plant-derived phytoestrogens also appear to have beneficial effects related to prevention of hepatic lipogenic signaling and steatosis in rodent models. Additionally, such compounds can completely overcome the hepatic consequences that result from estrogen deficiency. While published research strongly supports that estrogens, both endogenous and exogenous, can protect against hepatic lipogenic signaling that can contribute to the development of non-alcoholic fatty liver diseases and adverse weight gain, little research exists on elucidating the mechanism behind this protection. Various pathways have been suggested, including manipulation of both leptin and signal transducer and activator of transcription 3 (STAT3) signaling. However, the discovery of x-box protein 1 elicits the identification of another potential pathway through which estrogen may be working. While the supportive work is strong, further research is needed to determine the mechanism behind the protection by estrogens from hepatic lipogenesis and associated diseases.
Role of Estrogens in the Regulation of Liver Lipid Metabolism
Advances in experimental medicine and biology, 2017
Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.Many aspects of sex difference...
Effects of estrogen on hyperglycemia and liver dysfunction in diabetic male rats
International journal of physiology, pathophysiology and pharmacology, 2012
To study the possible beneficial effect of estrogen (17β-estradiol E(2)) on hyperglycemia, oxidative stress and liver dysfunctions in STZ-induced diabetic rats. A total of 40 albino male rats were randomly divided into four groups: a control group (I), a diabetic group (II), a group given 17β estradiol (E(2)) for 15 days (III), and a diabetic group given E(2) for 30 days (IV). Diabetes was induced in the rats by 65 mg/kg streptozosin (STZ) via an intraperitoneal (i.p.) injection. E(2) was given in a dose of 500ug/kg/day by oral gavage. E(2) administration significantly lowered plasma glucose levels, increased plasma insulin levels, and improved glucose tolerance of groups III and IV. In addition, E(2) enhanced glutathione peroxidase (GPX) and reduced lipid peroxidation in the hepatic tissues (as compared to diabetic rats). E(2) caused significant decrease of plasmatic phosphatase alkaline (PAL), lactate dehydrogenase (LDH), aspartate and lactate transaminases (AST and ALT) activitie...
Steroids, 2016
Low levels of plasma estrogens are associated with weight-gain, android fat distribution, and a high prevalence of obesity-related comorbidities such as glucose intolerance and type II diabetes. The mechanisms underlying the association between low levels of estrogens and impaired glucose homeostasis are not completely understood. To begin to test this, we used three-month-old female C57BL/6J mice that either underwent ovariectomy (OVX) or received a sham surgery (Sham), and we characterized glucose homeostasis. In a subsequent series of experiments, OVX mice received estradiol treatment (OVX+E2) or vehicle (OVX) for 6 consecutive days. As has been previously reported, lack of ovarian hormones resulted in dysregulated glucose homeostasis. To begin to explore the mechanisms by which this occurs, we characterized the impact of estrogens on insulin secretion and degradation in these mice. Insulin secretion and plasma insulin levels were lower in OVX mice. OVX mice had lower levels of p...
Molecular Mechanisms of Estrogen Receptors' Suppression of Lipogenesis in Pancreatic β-Cells
Endocrinology, 2012
The gonadal steroid, 17-estradiol (E2), suppresses pancreatic islet fatty acid and glycerolipid synthesis and prevents -cell failure in rodent models of type 2 diabetes. -Cell estrogen receptors (ER) mediate these actions by suppressing the expression and enzymatic activity of fatty acid synthase (FAS). Here, we explored the mechanism of FAS suppression. We show that E2, and pharmacological agonists for ER␣, ER, and the G protein-coupled ER, suppress mRNA and protein expression of the transcriptional regulators of FAS, namely, sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate response element binding protein (ChREBP) in insulinsecreting INS-1 cells. ER suppress SREBP1c and ChREBP mRNA and protein expression via an extranuclear localization. Using two mouse lines with pancreas-specific null deletion of either ER␣ or the signal transducer and activator of transcription 3 (STAT3), we show that ER␣ activation in vivo reduces SREBP1c and ChREBP mRNA expression via a direct islet action involving STAT3 activation. The master regulators of lipogenesis, liver X receptor (LXR) ␣ and , transcriptionally up-regulate SREBP1c and ChREBP. We find that activation of ER␣, ER, and G protein-coupled ER suppresses LXR's mRNA expression in INS-1 cells. We also observe that activation of ER␣ in mouse islets in vivo suppresses LXR mRNA in a STAT3-dependent manner. Finally, we show that E2 also activates and uses AMP-activated protein kinase in INS-1 cells to suppress SREBP1c protein expression. This study identifies extranuclear ER pathways involving STAT3 and AMP-activated protein kinase in the genetic control of lipogenesis with therapeutic implications to protect -cells in type 2 diabetes.