Joint MiRNA/mRNA expression profiling reveals rhanges consistent with development of dysfunctional corpus luteum after weight gain

<div><p>Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (<i>Chlorocebus aethiops</i>) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7–9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.</p></div

Vitamin D deficiency and cardiovascular disease in postmenopausal women: contributions from human and nonhuman primate studies.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death among American postmenopausal women and all adult Americans. The medical community and the lay community have recently become intrigued with vitamin D and its potential role in reducing the risk of CVD. Research findings from multiple retrospective studies, few prospective studies, and recent nonhuman primate studies have been inconsistent and conflicting. The objective of this study is to review what is known about the topic, what questions remain unanswered, and where the research community should be focusing. METHODS: A literature search was conducted through PubMed and Google Scholar up to August 1, 2014. One hundred six articles, including 18 double-blind, placebo-controlled, randomized clinical trials, relevant to the study topic were identified. All studies were stratified based on study design and primary outcome. The effects of vitamin D on CVD were reviewed and summarized. RESULTS: Although there is an abundance of observational studies suggesting an association with CVD protection, the most well-controlled randomized human trial data available show no benefit of vitamin D on CVD. However, highly controlled nonhuman primate studies indicate a beneficial relationship. CONCLUSIONS: Well-designed research, with CVD as primary outcome, is needed to help bridge the gap in our knowledge on this topic. In the meantime, caution should be applied to avoid overdiagnosis and overtreatment of vitamin D deficiency

Common Iliac Artery Vitamin D Receptor Expression Patterns During the Development of Atherosclerosis in Postmenopausal Nonhuman Primates

Objective: The results of recent studies suggest that vitamin D receptor (VDR) expression in the coronary arteries of female cynomolgus monkeys is negatively associated with atherosclerosis extent and severity. The objective of this study is to assess the changes in VDR expression in the common iliac arteries of postmenopausal monkeys during the development of atherosclerosis. Design: After 32 months of consuming an atherogenic diet, 37 premenopausal monkeys underwent ovariectomy. The same diet was then consumed for an additional 32 months until necropsy. Atherosclerosis extent and VDR expression were measured in the left iliac artery (LCI) at the time of ovariectomy, and in the right common iliac artery (RCI) at necropsy. Atherosclerosis severity (American Heart Association grading system) and VDR expression (VDR H-score) were quantified. Results: Despite increasing atherosclerosis over the course of the study, the total mean (SD) VDR H-score was significantly higher in the RCI in postmenopausal monkeys after consuming the athrogenic diet for a total of 64 months compared to the LCI of premenopausal monkeys who consumed the diet for 32 months (152.62[18.55] vs. 126.15[22.13], p\u3c.001). There was a significant positive correlation between the absolute (and percentage) change in total H-score and absolute change of AHA severity from preto post-menopause (Absolute: r=0.43, p=.008; Percentage: r=0.44, p=.007). Conclusion: Overall, contrary to our expectation, VDR expression was significantly increased in direct correlation with atherosclerosis increase in postmenopausal monkeys. A higher increase in VDR expression, from pre- to post-menopause, correlated with more severe atherosclerotic changes in the common iliac arteries

The Association between Common Iliac Artery Vitamin D Receptor Expression and Atherosclerosis in Postmenopausal Nonhuman Primates

Objective: The vitamin D receptor (VDR) has been localized to many tissues in the cardiovascular system including the coronary arteries of female nonhuman primates. The objective of the current study is to determine whether VDR expression in a peripheral artery (common iliac) is associated with atherosclerosis extent and severity in a cohort of postmenopausal cynomologus monkeys. Design: For 32 months, premenopausal cynomolgus monkeys (n=37) consumed an atherogenic diet containing a women’s equivalent of 1,200 mg/day of elemental calcium and 1,000 IU/day of vitamin D. After 32 months, the monkeys were ovariectomized and consumed the diet for an additional 32 months until artery specimens were collected at necropsy. Cross sections of the iliac artery were immunohistochemically stained for the VDR. Atherosclerosis extent was assessed by measuring iliac artery intimal (plaque) area (IA) and maximal intimal plaque thickness (MXIT). Plaque severity was determined using American Heart Association (AHA) atherosclerosis severity grades. Results: In the common iliac artery, a significant 65POSTER PRESENTATIONS observed compared to controls after cancer treatment. Conclusion: Our results suggest that cancer treatment increase bone loss in postmenopausal women with cervical and endometrial cancer.Positive correlation was observed between the proportion of VDR negative cells and plaque size (both cross-sectional area [r=0.578,

Response to an Adequate Dietary Intake of Vitamin D3 Modulates the Effect of Estrogen Therapy on Bone Density.

INTRODUCTION: This study analyzed associations between plasma vitamin D(3) (25OHD(3)) and bone mineral density (BMD) and whether the effects of conjugated equine estrogens (CEE) on BMD are modulated by 25OHD(3). METHODS: Fifty cynomolgus monkeys were fed a diet containing 25OHD(3) (providing a woman\u27s equivalent of 1000 IU/day of 25OHD3). The monkeys underwent bilateral oophorectomy and were randomized to either CEE (equivalent of 0.45 mg/day) (n=25) or placebo (n=25) and continued receiving the same diet. 25OHD(3) and BMD were measured at randomization and after 6 months. BMD also was measured after 20 months (equivalent to 6 human years). Associations between 25OHD(3) and BMD were subsequently analyzed. RESULTS: Baseline 25OHD(3) plasma concentrations varied from 26 to 95 ng/mL (mean±standard deviation [SD] 54 ± 15 ng/mL). Higher plasma concentrations of 25OHD(3) were associated with a significantly increased BMD. Monkeys on both CEE and placebo had increased BMD over 20 months; however, the increase was not significantly different (0.034 g/cm(2) vs. 0.020 g/cm(2), respectively; p=0.064). The 20-month BMD increased significantly with CEE treatment in those with higher vs. lower 25OHD(3) concentrations (p=0.027). The percent change in BMD over 20 months also increased significantly with CEE treatment in those with higher vs. lower 25OHD(3) concentrations (p=0.018). A higher 25OHD(3) concentration had no significant effect on BMD in those receiving placebo. CONCLUSIONS: Monkeys fed a diet containing 1000 IU/day equivalent of 25OHD(3) have a wide range of plasma 25OHD(3) concentrations. Those receiving CEE with higher 25OHD(3) concentrations had higher BMDs, suggesting 25OHD(3) and CEE have synergistic effects on BMD