Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome

Hevener, Andrea L.; Clegg, Deborah J.; Mauvais-Jarvis, Franck

doi:10.1016/j.mce.2015.05.020

Cited by 95 publications

(80 citation statements)

References 275 publications

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“…The relative expression of ERα and ERβ in adipose tissue has significant clinical relevance to women’s health via their regulation of adipose tissue distribution and function [1]. Presumably, maintenance of metabolically healthy SAT along with an adequate balance of ERs allows for efficient storage of potentially toxic lipids away from other important insulin-sensitive organs (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Aging in women typically leads to adverse changes in regional adiposity (i.e., increasing abdominal and decreasing femoral fat mass) and increased cardiometabolic risk [1]. The extent to which the age-related changes in adiposity and cardiometabolic risk in women are mediated by the loss of endogenous estrogens remains elusive.…”

Section: Introductionmentioning

confidence: 99%

“…Such menopause-related differences in ER expression could be the result of aging, estrogen deficiency, or changes in body fat distribution, but to our knowledge this has not yet been studied. Age-or menopause-related changes in ERs could have profound effects on estrogen physiology and the progression of metabolic syndrome [1]. ERα and ERβ have distinct, often opposing, actions suggesting the relative proportions of ERα and ERβ are important to the tissue-specific response to estrogen [2, 5].…”

Section: Introductionmentioning

confidence: 99%

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Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression

Park¹,

Erickson²,

Bessesen

et al. 2017

Steroids

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Objectives Changes in estrogen receptor (ER) expression likely underlie differential metabolic effects of estrogen in pre-and postmenopausal women. The aim of the current study was to determine whether ER gene expression in abdominal and femoral subcutaneous adipose tissue (SAT) was associated with age, menopause, or regional adiposity. Methods We studied pre-and post-menopausal (n=23 and 22, respectively; age 35–65 y) normal weight (mean±SD; BMI 23.7±2.5 kg/m2) women with similar total fat mass. Abdominal and femoral SAT ERα (ESR1) and ERβ (ESR2) mRNA expression was determined by qPCR. Results Total fat mass did not differ between pre-and postmenopausal women (22.7±5.3 vs. 21.7±5.3 kg). Compared to premenopausal women, ESR1 and the ratio of ESR1 to ESR2 were lower (p≤0.05) in postmenopausal abdominal and femoral SAT. ESR1 and ESR1:ESR2 were inversely associated with age in abdominal SAT (r=−0.380 and r=−0.463, respectively; p<0.05) and femoral SAT (r=−0.353 and r=−0.472, respectively; p<0.05). ESR2 was not related to age or menopause. The inverse association between ESR1 and age persisted after adjusting for trunk fat mass, estradiol, or leptin. Conclusion Among healthy pre-and postmenopausal women, increased age was associated with a decreased balance of ERα to ERβ in abdominal and femoral subcutaneous adipose tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression

Park¹,

Erickson²,

Bessesen

et al. 2017

Steroids

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“…Comparisons of rats or mice that have been gonadectomized to remove the acute effects of gonadal hormones after adulthood have corroborated the important role of gonadal hormones in the hypothalamic-pituitary axis and effects on energy intake and expenditure [9,11,12]. In the mouse, genetic ablation of genes for the estrogen receptor have further defined the effects of estrogen on feeding behavior, muscle metabolism, glucose homeostasis and other factors that impact fat storage [19]. However, studies that utilize gonadectomy of adult animals to study the effects of gonadal hormones on obesity do not control for the effects of gonads during development, often referred to ‘organizational effects.’ These include the development of male and female secondary sex characteristics and the impact of differential gonadal hormone levels during development, which may include differences in muscle mass and establishment of fat depots.…”

Section: Approaches To Dissect Gonadal Hormone and Sex Chromosome mentioning

confidence: 99%

Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities

Reue

2017

Physiology & Behavior

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Obesity is a world-wide problem, and a risk factor for cardiovascular disease, diabetes, cancer and other diseases. It is well established that sex differences influence fat storage. Males and females exhibit differences in anatomical fat distribution, utilization of fat stores, levels of adipose tissue-derived hormones, and obesity co-morbidities. The basis for these sex differences may be parsed into the effects of male vs. female gonadal hormones and the effects of XX vs. XY chromosome complement. Studies employing mouse models that allow the distinction of gonadal from chromosomal effects have revealed that X chromosome dosage influences food intake, which in turn affects adiposity and the occurrence of adverse metabolic conditions such as hyperinsulinemia, hyperlipidemia, and fatty liver. The identification of X chromosome dosage as a player in the behavior and physiology related to obesity suggests novel molecular mechanisms that may underlie sex differences in obesity and metabolism.

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“…As a key regulator of energy and glucose homeostasis, estrogen receptor α (ERα) is now considered a relevant target to develop new therapeutic approaches for obesity‐related metabolic disorders, such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) . Understanding the mechanisms involved in ERα‐mediated metabolic protection thus remains a crucial challenge to optimize pharmacologic strategies for ERα selective modulation …”

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confidence: 99%

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

et al. 2019

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Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion ( LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐ knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

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Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome

Cited by 95 publications

References 275 publications

Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression

Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression

Sex differences in obesity: X chromosome dosage as a risk factor for increased food intake, adiposity and co-morbidities

Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

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