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High-fat and high-sucrose diet impairs female reproduction by altering ovarian transcriptomic and metabolic signatures

ABSTRACT: Excessive energy intake in modern society has led to an epidemic surge in metabolic diseases, such as obesity and type 2 diabetes. These disorders pose profound threats to women’s reproductive health. However, the precise impact and underlying pathogenesis of energy excess on female reproduction remain unclear. In this study, we established an obese and hyperglycemic female mouse model induced by a high-fat and high-sucrose (HFHS) diet, mimicking the modern lifestyle of overnutrition. These mice displayed marked reproductive dysfunction, including elevated serum testosterone levels, irregular estrous cycles, and impaired folliculogenesis. Analysis of the ovarian metabolome of the HFHS mice revealed a pronounced disturbance in amino acid metabolism. Transcriptomic profiling of these ovaries identified dysregulated genes involved in steroid hormone biosynthesis and glucolipid metabolism. Further multi-omic analysis unveils aberrations in ovarian arginine biosynthesis metabolism induced by HFHS diet. Notably, comparisons between HFHS mice and a cohort of women with polycystic ovary syndrome (PCOS) identified analogous reproductive and metabolic signatures. Therefore, our results provide direct in vivo evidence for the detrimental effects of overnutrition on female reproduction and offer insights into the metabolic underpinnings of PCOS.

ORGANISM(S): Mus musculus

PROVIDER: GSE240547 | GEO | 2024/02/26

REPOSITORIES: GEO

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High-Fat High-Sugar Diet Induces Polycystic Ovary Syndrome in a Rodent Model

Project description:Obesity has been linked with a host of metabolic and reproductive disorders including polycystic ovary syndrome (PCOS). While a distinct link exists between obesity and PCOS, the exact pathogenesis of the disease remains less understood and limited research has explored the impact of diet on the development of PCOS. With the primary symptoms of PCOS including hyperandrogenism, anovulation, and polycystic ovaries, most animal models utilize androgen treatment to effectively induce PCOS. However, these models fail to address the underlying causes of disease symptoms and do not effectively demonstrate the metabolic features of the disease such as hyperinsulinemia. Here, we present a novel rodent model of diet-induced obesity that recapitulates both the metabolic and reproductive phenotypes of human PCOS. In utilizing a high-fat high-sugar (HFHS) diet, we have created a model of PCOS that allows for the study of metabolic parameters and their impact on ovarian follicle development and reproductive health. Animals on the HFHS diet not only demonstrated signs of metabolic impairment, but they also developed polycystic ovaries and experienced irregular estrous cycling marked by an extended period spent in estrus. Though hyperandrogenism was not characteristic of HFHS diet animals as a group, testosterone levels were predictive of a polycystic ovarian morphology. Importantly, PCOS was induced similarly to the disease etiology in humans, allowing this model to offer the unique opportunity to study PCOS at its genesis rather than following the development of disease symptoms.

2017-06-01 | GSE83220 | GEO

Gene expression in rat ovaries treated with DHT

Project description:Polycystic ovarian syndrome (PCOS) is an endocrine disorder of the reproductive and metabolic axis in women during the reproductive age. In this study, we used a rat model exhibiting reproductive and metabolic abnormalities similar to human PCOS to unravel the molecular mechanisms underlining this complex syndrome. Female Sprague-Dawley rats were implanted with a silicone capsule continuous-releasing 5Î±-dehydrotestestrone (DHT) per day for 12 weeks to mimic the hyperandrogenic state in women with PCOS, and the control (CTL) groups received an empty capsule. The animals were euthanized at 15 weeks of age and the ovarian cortex tissues of both groups were used for transcriptome profile analysis.

2016-07-03 | E-GEOD-59456 | biostudies-arrayexpress

Gene expression in rat ovaries treated with DHT

2016-01-01 | GSE59456 | GEO

Proteome of follicular Fluid from lean and overweight/obese women with PCOS and that of healthy controls

Project description:Polycystic ovary syndrome (PCOS) is typically characterized by oligo or anovulation, hyperandrogenism and polycystic ovarian morphology, affecting 5-20% of women of reproductive age [1]. It has drawn significant attention as a major cause of anovulatory infertility and the syndrome of metabolic, reproductive and obstetrical disorders [2 ,+]. Due to heterogeneous clinical features and unclear pathogenesis of PCOS, the diagnosis and treatment strategies remain a matter of debate. To better understand the complex follicular development environment in PCOS, we conducted a TMT-based quantitative proteomic study to compare the composition of proteins, pathways and molecular functions of FF from lean and overweight/obese women with PCOS and that of healthy controls.

2019-10-31 | PXD013937 | Pride

Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

Project description:The transgenerational maternal effects of PCOS in female progeny have been revealed. As there are evidence that a male equivalent of PCOS may exist, we asked whether sons born to mother with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a Swedish nationwide register-based cohort and a clinical case-control study from Chile we found that PCOS-sons are more often obese and dyslipidemic. Their serum miRNAs are found to potentially regulate PCOS-risk genes. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3. Small non-coding RNAs (sncRNAs) sequencing of F1-F3 sperm revealed distinct differentially expressed (DE) sncRNAs across generations in the androgenized, obese, and obese and androgenized lineages, respectively. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance highlighting a previously underappreciated risk of reproductive and metabolic dysfunction via the male germline transmission and potential molecular markers to study in future generations.

| EGAS00001007079 | EGA

Multiomics analysis reveals molecular abnormalities in granulosa cells of women with polycystic ovary syndrome

Project description:Polycystic ovary syndrome (PCOS) is the most common complex endocrine and metabolic disease in women of reproductive age. It is characterized by anovulatory infertility, hormone disorders, and polycystic ovarian morphology. Regarding the importance of granulosa cells (GCs) in the pathogenesis of PCOS, few studies have investigated the etiology at a single “omics” level, such as with an mRNA expression array or methylation profiling assay, but this can provide only limited insights into the biological mechanisms. Here, genome-wide DNA methylation together with lncRNA-miRNA-mRNA profiles were simultaneously detected in GCs of PCOS cases and controls. A total of 3579 lncRNAs, 49 miRNAs, 669 mRNAs, and 890 differentially methylated regions (DMR)-associated genes were differentially expressed between PCOS cases and controls. Pathway analysis indicated that these differentially expressed genes were commonly associated with steroid biosynthesis and metabolism-related signaling, such as glycolysis/gluconeogenesis. In addition, we constructed ceRNA networks and identified some known ceRNA axes, such as lncRNAs-miR-628-5p-CYP11A1/HSD17B7. We also identified many new ceRNA axes, such as lncRNAs-miR-483-5p-GOT2. Interestingly, most ceRNA axes were also closely related to steroid biosynthesis and metabolic pathways. These findings suggest that it is important to systematically consider the role of reproductive and metabolic genes in the pathogenesis of PCOS.

2021-03-08 | GSE168404 | GEO

Transcription profiling of human theca cells from women with polycystic ovary syndrome and normal theca cells treated with valproate

Project description:Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that affects 5-10% of reproductive aged women. The hallmark characteristic of PCOS is increased ovarian androgen synthesis. Previous studies by our laboratory demonstrated that increased androgen synthesis is a stable biochemical phenotype of PCOS theca cells which are the primary source of ovarian androgen production. The increase in theca cell steroidogenesis was due to an increase in expression of several steroidogenic enzymes including CYP17 and CYP11A but not StAR. Interestingly, the anti-epileptic drug valproic acid induces increased theca cell androgen synthesis and increased CYP17 and CYP11A mRNA levels. In this study we have characterized the gene expression profiles of theca cells obtained from normal or polycystic ovaries which were maintained in the absence (UNT) or presence (VPA) of valproic acid. The data identifed new candidate genes and novel signaling pathways which may contribute to the manifestation of PCOS phenotypes including increased androgen production. The experiments in this study were carried using the Affymetrix U133A and U133B oligonucleotide chips.

2007-08-13 | E-GEOD-1615 | biostudies-arrayexpress

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome

Project description:The effects of how obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring are unclear. We found that daughters of PCOS mothers are more likely to be diagnosed with PCOS in a Swedish nationwide register-based cohort and a clinical case-control study from Chile. Further, female mice (F0) with PCOS-like traits induced by late gestation injection of dihydrotestosterone, with and without obesity, produced female F1–F3 offspring with a PCOS-like reproductive and metabolic phenotypes. Sequencing of single MII oocytes from F1–F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of PCOS mothers and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

2019-10-30 | GSE133100 | GEO

CD38 regulates ovarian function and fecundity via NAD metabolism

Project description:Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD levels. However, the mechanisms underlying this loss of ovarian NAD are unclear. Here, we show that CD38, a NAD consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD metabolism and establishing the ovarian reserve, a critical process that dictates a female reproductive lifespan.

| MSV000092808 | MassIVE

DENND1A Desensitizes Granulosa Cells to FSH by Arresting Intracellular FSHR Transportation

Project description:Genome-wide association studies (GWAS) have identified polycystic ovary syndrome (PCOS)-associated loci, including DENND1A encoding a clathrin-binding protein involved in vesicle transport as a guanine nucleotide exchange factor. The effect of DENND1A on reproduction and whether it participates in follicle development disorder and androgen synthesis in PCOS remain unknown. Here, we demonstrated that DENND1A expression increased in ovarian granulosa cells (GCs) of PCOS patients and was positively correlated with serum testosterone concentration. We constructed a systemic transgenic Dennd1a mouse (TG mouse) model, which showed subfertility, irregular estrous cycles, and increased production of testosterone after PMSG stimulation. Moreover, TG mice showed hyporesponsiveness to PMSG with smaller ovary size and less well-developed follicles. Intracellular follicle-stimulating hormone receptor (FSHR) transport was disturbed by overexpression of Dennd1a, which promoted FSHR internalization and inhibited its recycling. Our findings revealed the reproductive function of DENND1A and the underlying mechanisms, which provided new insights into the PCOS pathogenesis and contributing to drug design for PCOS treatment.

2023-07-05 | GSE236248 | GEO

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