The role of sex hormones in adiposity and insulin resistance in the Aromatase Knockout mouse (ArKO)model

Abstract

Sex hormones such as estrogens and androgens are known to influence the development of adiposity and insulin resistance, which contribute to many disease processes including the Metabolic Syndrome. Adipose tissue plays a crucial role in energy homeostasis. It was once thought as merely an organ for lipid storage, but it is now regarded as an endocrine organ (Kershaw and Flier, 2004). Adiposity seen in obesity, is linked to over-nutrition and decreased energy output, which leads to an increase in the size and number of adipocytes. This results in the release of adipokines and excess free fatty acids into the circulation and subsequent ectopic accumulation of excess lipids in peripheral tissue eg. skeletal muscle and liver. This can influence insulin sensitivity by causing inflammation and interrupting the insulin signaling pathways leading to decreased glucose uptake (Nawrocki and Scherer, 2004). To research the effects of sex hormones on adiposity and insulin resistance, we studied Aromatase knockout (ArKO) mice which are unable to convert androgens to estrogens. In this thesis we defined the individual and combined roles of estrogens, androgens, progesterone and HRT drug Tibolone in the modulation of adipose tissue accumulation and lipid production in the absence of aromatase. We discovered the estrogenic component of Tibolone was the significant factor in reducing adiposity. Our study has confirmed the efficacy of tibolone as an HRT to reduce adipose tissue accumulation following menopause and also shows that aromatisation of tibolone is not required to elicit these estrogenic effects. Our data confirmed a positive correlation between estrogen, adipose tissue loss and consequently the regulation of leptin in ArKO mice. Sexually dimorphic differences were observed in the levels of adiponectin, TNFα and IL6. We detected an unexpected increase in levels of pro-inflammatory adipokines and decreases in adiponectin levels after estrogen treatment only in the female ArKO mice, despite reduced adiposity. This study therefore presents vital information as to the sexually dimorphic role of estrogen on adipokine regulation. We also discovered sexually dimorphic differences in the ArKO insulin resistance phenotype. Male ArKO mice developed and maintained glucose and pyruvate intolerance and insulin resistance at all ages. This was attributed to the development of hepatic insulin resistance, affecting gluconeogenesis and insulin signaling. Estrogen replacement was able to improve all aspects of this phenotype. Female ArKO mice developed and maintained only glucose intolerance, without developing pyruvate intolerance or insulin resistance, throughout a twelve-month life span. Contrary to males, estrogen replacement had an unexpected effect on the three month-old female ArKO mice, causing insulin resistance and further glucose intolerance. However, by six and twelve months of age, estrogen was able to improve all phenotypes. Lastly, we also noted novel decreases in two microRNAs the omental adipose tissue of the ArKO mice, which target genes involved in lipid metabolism and insulin signalling. These changes suggest a role for estrogen in post-transcriptional modification. Understanding the mechanisms by which sex hormones act on the metabolic pathways will provide insights into understating the pathogenesis of metabolic syndrome established in sex hormone related conditions such as menopause