Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome

Romero-Aleshire, Melissa Jill; Diamond‐Stanic, Maggie; Hasty, Alyssa H.; Hoyer, Patricia B.; Brooks, Heddwen L.

doi:10.1152/ajpregu.90762.2008

Cited by 66 publications

(82 citation statements)

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“…Here we show that during perimenopause ANG II infusion does not induce hypertension. These results build upon our previous studies in which we investigated how the transition from perimenopause to menopause impacted the development of the metabolic syndrome (34). We demonstrated that VCD-treated mice given a high-fat diet gained significantly more weight and had impaired glucose tolerance compared with cycling female mice on a high-fat diet.…”

Section: Discussionsupporting

confidence: 83%

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Pollow

Romero-Aleshire

Sánchez

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Pollow DP, Romero-Aleshire MJ, Sanchez JN, Konhilas JP, Brooks HL. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. Am J Physiol Regul Integr Comp Physiol 309: R1546 -R1552, 2015. First published October 21, 2015 doi:10.1152/ajpregu.00170.2015.-Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg Ϫ1 ·min Ϫ1 ) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17␤-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17␤-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17␤-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause.aquaporin-2; glomerular hypertrophy; collecting duct; estrogen PREMENOPAUSAL FEMALES are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease incidence and severity (20). Similarly, resistance to ANG II-induced hypertension has been demonstrated in female rodents. Ovariectomy (the abrupt induction of menopause via the removal of gonads) removes this resistance to ANG II, resulting in a robust ANG II-induced hypertensive response (39). Pharmacological inhibition or genetic ablation of estrogen receptors also increases the hypertensive response to ANG II infusion, suggesting that the loss of 17␤-estradiol signaling during menopause is in part responsible for the shift in blood pressure regulation (40).R...

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Section: Discussionsupporting

confidence: 83%

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Pollow

Romero-Aleshire

Sánchez

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In mouse models, using ovarian failure to mimic the onset of menopause corresponds with an increase in insulin resistance (42). In this mouse model, the onset of insulin resistance was prevented following ovarian failure using estrogen replacement (17-␤ estradiol) therapy, thus further proving the importance of sex hormones on metabolic disease manifestation (42).…”

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confidence: 81%

“…One factor that contributes to this is menopause. Clinically, during menopause there is a shift in the circulating estradiol levels and an increase in the ratio of androgens that places women at increased risk for CVD and Type 2 diabetes (36,42). Specifically, low levels of sex hormone binding globulin (SHBG), high free androgen levels, and low estradiol levels have been implicated in the CVD risk in perimenopausal women (48).…”

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confidence: 99%

“…Specifically, low levels of sex hormone binding globulin (SHBG), high free androgen levels, and low estradiol levels have been implicated in the CVD risk in perimenopausal women (48). In mouse models, using ovarian failure to mimic the onset of menopause corresponds with an increase in insulin resistance (42). In this mouse model, the onset of insulin resistance was prevented following ovarian failure using estrogen replacement (17-␤ estradiol) therapy, thus further proving the importance of sex hormones on metabolic disease manifestation (42).…”

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confidence: 99%

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Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

Griffin

Lanzetta

Eter

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses. diabetes; high-fat diet; myelopoisis; obesity; sexual dimorphism GLOBAL OBESITY RATES have risen drastically in the past several decades with around one in every three individuals currently categorized as obese (34). The overall incidence of obesityrelated diseases such as diabetes and cardiovascular disease (CVD) also continues to rise as a result (3a). Obesity manifests as the result of an imbalance of caloric intake and energy expenditure. A major contributing factor to the increase in obesity rates is an increase in the consumption of calorie-dense foods rich in saturated fatty acids (4). With increased consumption of high-fat foods, individuals accrue body fat and thus have an elevated risk of developing obesity-related diseases. In this brief review we will emphasize the effects of diet-induced obesity, focusing primarily on sexually dimorphic responses of high-fat diet (HFD) priming of the immune system. An individual's response to HFD is dependent on several factors including sex, age, and ethnicity. What has become increasingly striking is that there is a clear sexual dimorphism in obesity and diabetes rates. While obesity rates are higher in women (34), men have higher rates of cardiovascular disease (CVD) and Type 2 diabetes (30, 36), suggesting that females are protected from the adverse effects of obesity (30). This is of particular importance because when investigating diabetes and CVD, many preclinical studies have been performed in males alone, leaving gaps in our knowledge of sexually dimorphic responses to obesity (45). Therefore, guidelines and therapies are being created based on investigations in males but are being implemented in men and women (13).It is important to investigate males and females to understand the contributing factors to these sex-specific differences. Previous studies have focused on altered hormone environments, anatomical fat distribution (17, 19), and energy expenditure differences. Women have been found to have 10% higher total body fat content compared with males of the same body mass index (BMI) (15). This dimorphism is especially profound in poor socioeconomic conditions, whereas richer environments show a smaller variance in adiposity between the sexes (11). This suggests that estrogen largely influences fat accumulation regardless of socioeconomic status (11). Additionally, when adiposity matched, fema...

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“…As a result, VCD-treated mice undergo a gradual decrease in cyclicity and eventually enter persistent diestrus 2 months after treatment, resulting in increased levels of FSH and LH, reduced levels of progesterone, and undetectable amounts of estradiol (consistent with human menopause). 13 Because of the hypothesized role of menopause in several pathological conditions, the VCD mouse model has been used to study atherosclerosis, 14 insulin resistance, 15 neuroprotection after stroke, 16 and ovarian tumorigenesis. 17 When Craig et al 17 injected the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) under the bursa of VCD-treated mouse ovaries, 57% developed ovarian neoplasms, which were classified as Sertoli-Leydig tumors (a rare histological subtype of sex cord stromal tumors).…”

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confidence: 99%

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer

et al. 2011

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Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome

Cited by 66 publications

References 40 publications

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause

Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer

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