scholarly journals Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1590-1600 ◽  
Author(s):  
Camila Manrique ◽  
Guido Lastra ◽  
Francisco I. Ramirez-Perez ◽  
Dominic Haertling ◽  
Vincent G. DeMarco ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Vascular Reactivity ◽  
Control Diet ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Vascular Stiffening

Abstract Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

Abstract P200: Endothelial Estrogen Receptor Alpha Does Not Protect Female Mice Against Western Diet Induced Vascular Stiffness

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Camila Manrique ◽  
Guido Lastra ◽  
Dominic Haertling ◽  
Vincent DeMarco ◽  
Annayya Aroor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Ex Vivo ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Cell Stiffness ◽  
Whole Body ◽  
Receptor Alpha

Background: Women with obesity, insulin resistance and type 2 diabetes mellitus (T2D) lose the cardiovascular disease protection normally afforded by female sex hormones, but the underlying mechanism(s) remain unknown. Increases in vascular stiffness occur with aging, but conditions of insulin resistance such as obesity and T2D are characterized by accelerated development of this phenomenon. Under physiological conditions, vascular estrogen signaling via estrogen receptor alpha (ERα) increases endothelial bioavailable nitric oxide which decreases stiffness. Nevertheless, in conditions of insulin resistance, the effects of ERα signaling may be deleterious. Methods: We used a novel rodent model lacking ERα in the endothelial cells (ECERαKO). The genomic region encompassing exon 3 of the ERα gene was flanked by loxP sites. ECERαKO mice were generated by crossing ERα doubled floxed mice with Cad-Cre+ mice (VE-Cadherin promoter driving expression of Cre-recombinase). Female ECERαKO mice and littermates were fed a high fructose/high sucrose (Western diet - WD) for 8 weeks. The WD diet consisted of 60% fat and 20% sucrose. At the end of the intervention period, mice underwent in vivo and ex vivo assessment of vascular stiffness. Results: The absence of EC ERα did not impact whole body insulin sensitivity (examined by HOMA-IR). Females lacking the endothelial specific ERα had less vascular stiffness when assessed in vivo via aortic pulse wave velocity than the littermates fed with a WD (3.43 ± 0.184 m/s vs. 4.080 ± 0.172 m/s, p<0.05). Similarly, ex vivo evaluation of aortic endothelial cell stiffness using atomic force microscopy (AFM) revealed increased stiffness in the females with intact EC ERα when compared with ECERαKO females (1.91 ± 0.60 kPa vs. 13.09 ± 2.61 kPa ) (p<0.05). Resistant vessel (femoral artery) also revealed less stiffness (decreased modulus of elasticity) in ECERαKO mice fed a WD. Conclusion: Endothelial ERα does not protect females from vascular stiffness induced by a WD. Indeed, the present data suggest a predisposition toward protection of rodent lacking ERα in conditions of insulin resistance.

scholarly journals FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4020-4032 ◽  
Author(s):  
Alli M. Nuotio-Antar ◽  
Naravat Poungvarin ◽  
Ming Li ◽  
Michael Schupp ◽  
Mahmoud Mohammad ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fatty Liver ◽  
Binding Protein ◽  
Western Diet ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Chow Diet ◽  
Fatty Acid Binding ◽  
Constitutively Active

Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance.

scholarly journals Knockout of glucose transporter GLUT6 has minimal effects on whole body metabolic physiology in mice

2018 ◽  
Vol 315 (2) ◽  
pp. E286-E293 ◽  
Author(s):  
Frances L. Byrne ◽  
Ellen M. Olzomer ◽  
Robert Brink ◽  
Kyle L. Hoehn
Keyword(s):  
Glucose Transporter ◽  
Gene Expression Pattern ◽  
Western Diet ◽  
Whole Body ◽  
Chow Diet ◽  
Mouse Development ◽  
Wild Type Littermate ◽  
Female Mice ◽  
Transporter Family ◽  
Metabolic Physiology

Glucose transporter 6 (GLUT6) is a member of the facilitative glucose transporter family. GLUT6 is upregulated in several cancers but is not widely expressed in normal tissues. Previous studies have shown that GLUT6 knockdown kills endometrial cancer cells that express elevated levels of the protein. However, whether GLUT6 represents a viable anticancer drug target is unclear because the role of GLUT6 in normal metabolic physiology is unknown. Herein we generated GLUT6 knockout mice to determine how loss of GLUT6 affected whole body glucose homeostasis and metabolic physiology. We found that the mouse GLUT6 ( Slc2a6) gene expression pattern was similar to humans with mRNA found primarily in brain and spleen. CRISPR-Cas9-mediated deletion of Slc2a6 did not alter mouse development, growth, or whole body glucose metabolism in male or female mice fed either a chow diet or Western diet. GLUT6 deletion did not impact glucose tolerance or blood glucose and insulin levels in male or female mice fed either diet. However, compared with wild-type littermate controls, GLUT6 null female mice had a relatively minor decrease in fat accumulation when fed Western diet and had a lower respiratory exchange ratio when fed chow diet. Collectively, these data show that GLUT6 is not a major regulator of whole body metabolic physiology; therefore, GLUT6 inhibition may have minimal adverse effects if targeted for cancer therapy.

scholarly journals Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance

2018 ◽  
Author(s):  
Frances R. Belmonte ◽  
Nikolaos Dedousis ◽  
Ian Sipula ◽  
Nikita A. Desai ◽  
Aatur D. Singhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Gain ◽  
Hepatic Steatosis ◽  
Inflammatory Markers ◽  
Western Diet ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Chow Diet ◽  
Female Mice ◽  
Glucose Clearance

AbstractPetite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 removal alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females were protected against obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased gene expression of inflammatory markers in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.

Cystamine reduces vascular stiffness in Western diet-fed female mice

2021 ◽  
Author(s):  
Francisco I. Ramirez-Perez ◽  
Francisco J. Cabral-Amador ◽  
Adam T. Whaley-Connell ◽  
Annayya R Aroor ◽  
Mariana Morales-Quinones ◽  
...  
Keyword(s):  
Tissue Transglutaminase ◽  
Vascular Wall ◽  
Aortic Pulse Wave Velocity ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Mesenteric Arteries ◽  
Chow Diet ◽  
Obese Women ◽  
Arterial Stiffening ◽  
Female Mice

Consumption of diets high in fat, sugar and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Obese women are more prone to develop arterial stiffening leading to more frequent and severe CVD compared to men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a non-specific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 weeks starting at four weeks of age. The second was fed a WD for the same 43 weeks, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/d) in the drinking water during the last eight weeks on the diet (WD+C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- vs. CD-fed mice, and reduced in WD+C vs. WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin/G-actin ratio, collagen compaction capacity and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely due to its TG2 inhibitory capacity.

Abstract P068: Endothelial Mineralocorticoid Receptor Activation Promotes Endothelial And Vascular Stiffening In Western Diet Fed Female Mice Through Sgk1 Mediated Activation Of The Endothelial Sodium Channel

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Yan Yang ◽  
Zhe Sun ◽  
Annayya Aroor ◽  
Liping Zhang ◽  
Guanghong Jia ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Mineralocorticoid Receptor ◽  
Sodium Current ◽  
Receptor Activation ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Female Mice ◽  
Isolated Lung ◽  
Vascular Stiffening ◽  
Endothelial Stiffness

Over-nutrition/obesity predisposes persons, particularly women, to endothelial dysfunction and vascular stiffening. We have employed a clinically relevant model using female mice fed a high fat and high fructose diet (western diet, WD). These mice display high plasma aldosterone levels, endothelial stiffness and dysfunction and increased mineralocorticoid receptor (MR) expression in the vasculature. One potential mechanism by which MR activation may promote endothelial stiffness is through increased expression and activation of epithelial sodium channel (EnNaC) in endothelial cells (ECs) through mTOR2 mediated activation of serum and glucocorticoid regulated kinase 1(SGK1). In this investigation we observed that WD feeding in female mice for 16 wks caused endothelial (atomic force microscopy (AFM)), and aortic stiffening (PW analysis) in concert with increased expression of EnNaC and SGK1 in the endothelium and EnNaC activation in ECs. Further, amelioration of WD induced EC and vascular stiffness was accomplished by EnNaC inhibition with low dose amiloride (1mg/kg/day in drinking water) over the 16 wks of WD. We then explored the idea that inhibition of SGK1 as well as specific deletion of ECMR and EnNaC decreases vascular EC stiffness accompanied by decreased sodium current in isolated lung ECs. Accordingly, female wild type and ECMR and EnNaC KO mice were fed a WD or control diet (CD) for 16 wks. Aortic and coronary artery EC stiffness, measured ex vivo by AFM, was increased in WD fed mice and this was prevented in ECMR and EnNaC KO models. Both ECMR and EnNaC KO mice fed a WD showed decreased amiloride sensitive sodium current in isolated ECs. Further, in cultured ECs , inhibition of SGK1 by a chemical inhibitor attenuated aldosterone mediated sodium currents. Collectively, these findings support the notion that a WD promotes ECMR mediated increases in SGK1 and associated EnNaC activity in ECs together with increased endothelial and vascular stiffness in females.

scholarly journals Sexual Dimorphism in Obesity-Associated Endothelial ENaC Activity and Stiffening in Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2918-2928 ◽  
Author(s):  
Jaume Padilla ◽  
Makenzie L Woodford ◽  
Guido Lastra-Gonzalez ◽  
Vanesa Martinez-Diaz ◽  
Shumpei Fujie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Sexual Dimorphism ◽  
Estrogen Receptor Α ◽  
Western Diet ◽  
Estrogen Signaling ◽  
Cellular Mechanisms ◽  
Arterial Stiffening ◽  
Female Mice ◽  
Vascular Stiffening

Abstract Obesity and insulin resistance stiffen the vasculature, with females appearing to be more adversely affected. As augmented arterial stiffness is an independent predictor of cardiovascular disease (CVD), the increased predisposition of women with obesity and insulin resistance to arterial stiffening may explain their heightened risk for CVD. However, the cellular mechanisms by which females are more vulnerable to arterial stiffening associated with obesity and insulin resistance remain largely unknown. In this study, we provide evidence that female mice are more susceptible to Western diet–induced endothelial cell stiffening compared with age-matched males. Mechanistically, we show that the increased stiffening of the vascular intima in Western diet–fed female mice is accompanied by enhanced epithelial sodium channel (ENaC) activity in endothelial cells (EnNaC). Our data further indicate that: (i) estrogen signaling through estrogen receptor α (ERα) increases EnNaC activity to a larger extent in females compared with males, (ii) estrogen-induced activation of EnNaC is mediated by the serum/glucocorticoid inducible kinase 1 (SGK-1), and (iii) estrogen signaling stiffens endothelial cells when nitric oxide is lacking and this stiffening effect can be reduced with amiloride, an ENaC inhibitor. In aggregate, we demonstrate a sexual dimorphism in obesity-associated endothelial stiffening, whereby females are more vulnerable than males. In females, endothelial stiffening with obesity may be attributed to estrogen signaling through the ERα–SGK-1–EnNaC axis, thus establishing a putative therapeutic target for female obesity-related vascular stiffening.

scholarly journals Western Diet Modulates Insulin Signaling, c-Jun N-Terminal Kinase Activity, and Insulin Receptor Substrate-1ser307 Phosphorylation in a Tissue-Specific Fashion

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1576-1587 ◽  
Author(s):  
Patrícia Oliveira Prada ◽  
Henrique Gottardello Zecchin ◽  
Alessandra Lia Gasparetti ◽  
Márcio Alberto Torsoni ◽  
Mirian Ueno ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Control Diet ◽  
Western Diet ◽  
Whole Body ◽  
Insulin Receptor Substrate ◽  
Tissue Specific

The mechanisms by which diet-induced obesity is associated with insulin resistance are not well established, and no study has until now integrated, in a temporal manner, functional insulin action data with insulin signaling in key insulin-sensitive tissues, including the hypothalamus. In this study, we evaluated the regulation of insulin sensitivity by hyperinsulinemic-euglycemic clamp procedures and insulin signaling, c-jun N-terminal kinase (JNK) activation and insulin receptor substrate (IRS)-1ser307 phosphorylation in liver, muscle, adipose tissue, and hypothalamus, by immunoprecipitation and immunoblotting, in rats fed on a Western diet (WD) or control diet for 10 or 30 d. WD increased visceral adiposity, serum triacylglycerol, and insulin levels and reduced whole-body glucose use. After 10 d of WD (WD10) there was a decrease in IRS-1/phosphatidylinositol 3-kinase/protein kinase B pathway in hypothalamus and muscle, associated with an attenuation of the anorexigenic effect of insulin in the former and reduced glucose transport in the latter. In WD10, there was an increased glucose transport in adipose tissue in parallel to increased insulin signaling in this tissue. After 30 d of WD, insulin was less effective in suppressing hepatic glucose production, and this was associated with a decrease in insulin signaling in the liver. JNK activity and IRS-1ser307 phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance induced by WD is tissue specific and installs first in hypothalamus and muscle and later in liver, accompanied by activation of JNK and IRS-1ser307 phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in the WD rats.

scholarly journals Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

2020 ◽  
Vol 9 (5) ◽  
Author(s):  
Emmanuel Guivarc'h ◽  
Julie Favre ◽  
Anne‐Laure Guihot ◽  
Emilie Vessières ◽  
Linda Grimaud ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Vascular Reactivity ◽  
Nuclear Gene ◽  
Estrogen Receptor Α ◽  
Protective Effects ◽  
Wild Type ◽  
Female Mice

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice. Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

scholarly journals Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

2011 ◽  
Vol 300 (6) ◽  
pp. G956-G967 ◽  
Author(s):  
Joel R. Garbow ◽  
Jason M. Doherty ◽  
Rebecca C. Schugar ◽  
Sarah Travers ◽  
Mary L. Weber ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Western Diet ◽  
Whole Body ◽  
Resonance Spectroscopy ◽  
Chow Diet ◽  
High Fat ◽  
Low Protein ◽  
Low Carbohydrate ◽  
Term Administration

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

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