Investigating obesity and adiposity-induced alterations to the human endometrium

Obesity is a highly prevalent chronic disease that poses a significant public health risk. Almost 42% of US adults are affected by obesity with women at higher risk for severe obesity than men (11.5 vs 6.9%). Obesity has a significant and complex impact on reproduction and is associated with menstrual irregularities,

anovulation, decreased rates of natural pregnancy, miscarriage, and infertility. While there are several known causes of infertility such as decreased ovarian reserve, male factor, and tubal disease, most require invasive and expensive procedures to achieve pregnancy, and, unlike obesity, very few are modifiable. Obesity is

commonly associated with anovulation-related causes of infertility but has been shown to impact all levels of the reproductive axis including the hypothalamus, pituitary, ovary, and endometrium. While there are far fewer studies on the endometrium than on other tissues, there are data from both human primary cells and mouse

models of obesity that implicate the endometrium in obesity-related infertility, mostly through defects in endometrial decidualization, the process by which the endometrium prepares itself for implantation in the luteal-phase of the menstrual cycle. There are two fundamental obstacles that have limited the ability to

understand the link between obesity, endometrial function, and infertility : 1) lack of comprehensive phenotyping isolating obesity from other co-occurring conditions that impact the endometrium such as PCOS and 2) reliance solely on BMI to study obesity. While obesity is most often singularly defined as a body mass

index (BMI) of ≥30 kg/m2, the sole use of BMI to categorize obesity-associated risks fails to consider the heterogeneity of the disease. The overall objective of this proposal is to assess the impact of obesity and adiposity as assessed by multiple parameters on the luteal-phase endometrium. We will include a cohort of

extensively-phenotyped women allowing for disentanglement of commonly co-occurring endocrine and metabolic disorders that have confounded prior studies. We hypothesize that obesity is associated with modified endometrial transcription and cellular subpopulations resulting in an altered proteomic profile and

aberrant decidualization. To test this hypothesis, in aim 1 we perform single-nuclear sequencing (snRNA-seq) on endometrial samples from women with and without obesity to comprehensively understand how pathologic adiposity might influence alterations in cellular populations. In aim 2 we will perform liquid chromatography

mass-spectrometry (LC-MS) to assess for altered proteomic profiles. Finally, in aim 3 we will perform functional endometrial assays to correlate transcriptomic and proteomic signatures with functional markers of endometrial dysfunction. These pilot experiments will provide novel insight into the well-known association of obesity with

infertility and early pregnancy loss, guiding planning for large scale validation and mechanistic studies.