Examining the relationship between menstrual cycle phase with metabolic control and adipose tissue microRNA expression

Abstract

The menstrual cycle is a fundamental biological rhythm governing physiology in females of a reproductive age. Regulated across an approximately 4-weekly duration, the menstrual cycle is characterised by cyclical fluctuations in ovarian hormones (estradiol, progesterone and testosterone) and pituitary hormones (luteinizing hormone sand follicle stimulating hormone). Ovarian hormones are metabolically active and exert key regulatory roles in metabolic control. Correspondingly, a variety of metabolic parameters undergo cyclical rhythmicity across the menstrual cycle, in association with the ovarian hormone milieu. However, female physiology is under-researched. Our understanding of variation in metabolic control across the menstrual cycle and the associated molecular mechanisms remains limited. Gaining a full understanding of how metabolic control varies across the menstrual cycle is crucial for the diagnoses, treatment and prevention of metabolic disease in females. Thus, the overall aim of this thesis is to examine cyclical variation in insulin resistance and associated metabolites across the menstrual cycle. Additionally, to examine the role of inflammatory markers and miRNAs as potential molecular mechanisms underpinning variation in metabolic control across the menstrual cycle.

Chapter 2 of this thesis demonstrates that rhythmic variation in insulin sensitivity, insulin, glucose and triglyceride are mediated by body mass index, physical activity and cardiorespiratory fitness. Chapter 3 extended on these findings to identify indices of body composition, fitness and physical activity levels are key modifiable risk factors mediating the variation in glucose, triglyceride, insulin sensitivity and cholesterol profiles across the menstrual cycle. Additionally, inflammatory markers varied across the menstrual cycle and associate with metabolite concentration, thereby identifying a potential mechanism which may underpin variation in metabolic control across the menstrual cycle.

To gain further insight into the molecular mechanisms underpinning observed rhythmicity in metabolic control across the menstrual cycle, Chapter 4 examines the effect of the menstrual cycle on adipose tissue microRNA expression. This determined that miR-495-5p was differentially expressed across menstrual cycle phases and miR-30c-5p was negatively associated with testosterone. Adipose tissue miRNAs with the strongest tendency for differential expression between menstrual cycle phases shared common targets related to insulin signalling pathways. Overall, this thesis contributes novel data characterising variation in metabolic control across the menstrual cycle. Finally, it identifies inflammation and miRNA expression as potential molecular mechanisms driving observed variation in metabolic control.