White adipose tissue functionality - Biological sex- and PCOS-related differences

Abstract

Adipose tissue is a dynamic energy storage and endocrine organ that plays a central role in metabolic regulation. Its function and distribution differ between the sexes, influencing the susceptibility to metabolic and endocrine disorders. One example is polycystic ovary syndrome (PCOS), a common endocrine disorder affecting women. This thesis explores how sex differences and androgen excess in PCOS shape the structure and function of adipose tissue and how these differences contribute to metabolic and hormonal imbalances. In Paper I, we demonstrated that macrophage-mediated intracellular collagen degradation is a critical process in healthy adipose tissue expansion. Our findings highlight that this process is disrupted in obese insulin resistant mice, associated with accumulation of collagen fragments within the tissue. These fragments may contribute to fibroinflammatory processes in obesity. In Paper II, we explored sex differences in adipose tissue extracellular matrix. Females showed a more adaptive subcutaneous adipose tissue remodelling, with lower tissue stiffness and higher adipocyte precursor cell proliferation than males. These findings were supported by human data, suggesting that sex-specific differences in collagen composition influence adipose tissue function and metabolic health. In Paper III, proteomic and phosphoproteomic analyses revealed that women with PCOS have altered muscle and adipose tissue protein expression, including changes in lipid metabolism, muscle fibre composition, and possibly mitochondrial functions. Electrical stimulation significantly impacted protein and phosphorylation profiles related to tissue remodelling. In Paper IV, we investigated adipose tissue dysfunction in two mouse models of PCOS. Chronic androgen exposure led to weight gain, adipocyte hypertrophy, reduced adipocyte precursor cells proliferation, and altered immune cell profiles, particularly in visceral adipose tissue. In contrast, prenatal androgen exposure led to a slightly increased fat mass without weight gain, enhanced adipocyte precursor cell proliferation and reduced adipogenesis. In vitro findings suggest that insulin resistance and macrophage-produced factors influence the functionality of adipocyte precursor cells in PCOS. In conclusion, differences in collagen remodelling, adipocyte precursor cell activity, and insulin signalling contribute to sex- and PCOS-related differences in adipose tissue functionality.