Weight cycling alters the immune composition of reproductive tissues, worsening infertility in female mice

Abstract

Abstract Obesity increases the risk of several comorbidities, such as infertility. While weight loss is highly recommended, maintaining a normal weight is typically unsuccessful, leading to weight regain (WR), which exacerbates inflammation and worsens comorbidities, compared to maintaining stable obesity, with reasons unknown. Hence, understanding the deleterious effects of WR holds great potential for decreasing the burden of metabolic diseases as well as infertility. Here, we hypothesized that WR has an adverse effect on female fertility compared to stable obesity. Females were fed high-fat diet for 14wks to establish obesity, then subjected to weight loss by reducing food intake by 30% for 2wks, followed by 3wks of free access to food to induce WR. Controls were age-matched mice that were freely fed high-fat diet without weight cycling. Females were assessed for immune composition of reproductive tissues or outcomes of mating with lean males. WR females showed lower pregnancy rate, smaller litter size and higher dystocia prevalence, resulting in in-uterus death of the fetuses, as compared to non-cycling females. Moreover, the uterus myometrium showed lipid accumulation only in WR females, suggesting a mechanism by which the fatty myometrium cannot contract properly leading to dystocia. In conclusion, weight cycling exacerbates obesity-related infertility. Further histology and flow cytometry analysis will determine whether and how immune cells in reproductive tissues are involved.