Origins of lifetime health around the time of conception: causes and consequences.

Both obesity and overweight are increasing worldwide and have detrimental influences on several human body functions including the reproductive health. In particular, obese women undergo perturbations of the ‘hypothalamic pituitary ovarian axis’, and frequently suffer of menstrual dysfunction leading to anovulation and infertility. Besides the hormone disorders and subfertility that are common in the polycystic ovary syndrome (PCOS), in obesity the adipocytes act as endocrine organ. The adipose tissue indeed, releases a number of bioactive molecules, namely adipokines, that variably interact with multiple molecular pathways of insulin resistance, inflammation, hypertension, cardiovascular risk, coagulation, and oocyte differentiation and maturation. Moreover, endometrial implantation and other reproductive functions are affected in obese women with complications including delayed conceptions, increased miscarriage rate, reduced outcomes in assisted conception treatments. On the contrary, weight loss programs through lifestyle modification in obese women, have been proven to restore menstrual cyclicity and ovulation and improve the likelihood of conception.

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Obesity as disruptor of the female fertility.

In the United States, 36.5% of women between the ages of 20 and 39 years are obese. This obesity results in not only metabolic disorders including type II diabetes and cardiovascular disease, but also impaired female fertility. Systemic and tissue-specific chronic inflammation and oxidative stress are common characteristics of obesity. This is also true in the ovary. Several studies have demonstrated that pro-inflammatory cytokines and reactive oxygen species alter estrous cyclicity, steroidogenesis and ovulation. Inflammation and oxidative stress also impair meiotic and cytoplasmic maturation of the oocyte which reduces its developmental competence for fertilization and pre-implantation embryo development. Interestingly, there is recent evidence that obesity- and/or polycystic ovary syndrome (PCOS)-dependent changes to the gut microbiome contributes to ovarian inflammation, steroidogenesis and the expression of mRNAs in the oocyte. However, several gaps remain necessitating future studies to identify inflammation, oxidative stress and gut microbiome mechanisms that reduce ovarian function and oocyte quality.

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Obesity induces ovarian inflammation and reduces oocyte quality

The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility. In the ovary, follicular degeneration occurs after folliculogenesis, with one dominant follicle reaching maturity every month. Here, by performing single cell RNA-seq of adult human follicles, the authors identify subclasses of granulosa and theca cell lineages, which correlate with the growth or degeneration of the follicles.

https://biblio.ugent.be/publication/8679771/file/8679772.pdf

Single-cell reconstruction of follicular remodeling in the human adult ovary.

Single-cell analysis provides insights into cellular heterogeneity and dynamics of individual cells. This Feature highlights recent developments in key analytical techniques suited for single-cell metabolic analysis with a special focus on mass spectrometry-based analytical platforms and RNA-seq as well as imaging techniques that reveal stochasticity in metabolism.

Deciphering Metabolic Heterogeneity by Single-Cell Analysis.

Context It is hypothesized that obesity adversely affects the ovarian environment, which can disrupt oocyte maturation and embryonic development. Objective This study aimed to compare oocyte gene expression profiles and follicular fluid (FF) content from overweight/obese (OW) women and normal-weight (NW) women who were undergoing fertility treatments. Design Using single-cell transcriptomic analyses, we investigated oocyte gene expression using RNA sequencing. Patients or Other Participants Eleven OW women and 13 NW women undergoing fertility treatments were enrolled. Main Outcome Measures Oocyte messenger RNA profiles as well as serum and FF hormone and lipid levels were assessed. Results OW women had significantly higher body mass index, body fat percentage, and serum homeostatic model assessment-insulin resistance index compared with NW women (P < 0.01). Serum leptin and C-reactive protein (CRP) levels as well as FF leptin, CRP, and triglyceride levels were increased (P < 0.05) in OW compared with NW women. Oocytes from OW women had increased expression of proinflammatory (CXCL2; P = 0.071) and oxidative stress-related (DUSP1; P = 0.051) genes but had decreased expression of GAS7 (fat metabolism; P = 0.065), TXNIP (oxidative stress; P = 0.055), and transcription factors ID3 (P = 0.075) and TWIST1 (P = 0.099) compared with NW women. Conclusions These findings provide evidence for the significant influence of body composition on oocyte transcript abundance in women undergoing hormonal induction to retrieve oocytes. They further identify the potential for maternal diet to influence oocyte gene expression. The preconception period is, therefore, an important window of opportunity to consider for lifestyle interventions.

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Matthew Cotter

Papers

Obesity Modulates Inflammation and Lipid Metabolism Oocyte Gene Expression: A Single-Cell Transcriptome Perspective.