The impact and reversibility of obesity-induced molecular and functional alterations to the human endometrium

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, miscarriage, and infertility. While there are several known causes of infertility, most require invasive and expensive procedures to achieve pregnancy, and, unlike obesity, very few are modifiable. Obesity impacts all levels of the reproductive axis including the hypothalamus, pituitary, ovary, and endometrium. While the effects of obesity on the endometrium are poorly defined or understood as compared to other tissues, both human primary cells and mouse models suggest that obesity has direct effects on the endometrium, primarily through disrupting endometrial cell decidualization. The current understanding of the relationship between obesity, endometrial function, and infertility is hindered by several important factors: 1) Utilization of heterogenous patient populations with obesity-associated reproductive and metabolic conditions known to impact the endometrium, such as PCOS, 2) reliance on BMI as the only measure of obesity, which fails to capture the complexity of the disease 3) utilization of insensitive or bulk molecular assessments of the endometrium which may not capture subtle or localized changes, 4) lack of understanding of how weight loss effects endometrial health and function. The overall objective of this proposal is to assess the impact of obesity on the proteomic, transcriptional, and cellular landscape of luteal-phase endometrium and to assess the reversibility and stability of these changes with significant weight loss achieved via bariatric surgery. The conceptual innovation of the proposed work is the inclusion of a cohort of extensively-phenotyped women allowing for disentanglement of commonly co-occurring endocrine and metabolic disorders that have confounded prior studies, and the assessment of endometrium at multiple timepoints post-bariatric surgery, thus capturing temporal alterations during and after significant weight loss. The technical innovation is the use of high-resolution proteomic and cutting-edge single-cell genomic techniques combined with established functional reproductive assays allowing for assessment of the isolated impact of obesity at a cellular level. We hypothesize that obesity induces alterations to endometrial cellular subpopulations with resultant variation in transcription and proteomic profiles that is partially reversible with significant weight loss even when a “normal” BMI is not achieved. We further hypothesize that measurements of obesity beyond BMI (adiposity distribution and adipokine levels) will correlate more accurately with cellular alterations and endometrial dysfunction. To test this hypothesis, in aim 1 we will characterize the molecular (proteomic, single cell-transcriptomic) and functional (decidualization/senescence) impact of obesity in a cohort of comprehensively phenotyped women with and without obesity. In aim 2, we will assess for reversibility and stability of these molecular and functional alterations in women who achieve significant weight loss following bariatric surgery.