Adipokines and the Metabolic Aspects of the Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age associated with a number of adverse metabolic sequealae. These women have an increased risk of insulin resistance and hyperinsulinemia, an increased risk of glucose intolerance and type 2 diabetes mellitus, dyslipidemia, subclinical atherosclerosis and vascular dysfunction, independent of BMI. With the epidemic of obesity, the PCOS phenotype is becoming ever more so prevalent and represents a clear and present health issue that needs to be addressed urgently. The studies describe for the first time the expression of visfatin and Retinol-Binding Protein 4 (RBP4) as well as adiponectin receptors, in corresponding sc and om human adipose tissues at both mRNA and protein levels. Also, it was shown that there was significant upregulation of visfatin and RBP4 as well as adiponectin receptors gene expression and protein in both these adipose tissue depots in overweight women with PCOS, including significantly higher circulatin visfatin and RBP4 levels, compared with matched controls. Furthermore, in isolated sc adipocytes, visfatin and RBP4 mRNA as well as adiponectin receptor(s) expression was significantly higher in age, BMI and WHR matched overweight PCOS women. Leptin was found to regulate om adipose tissue visfatin protein production and secretion, exhibiting a 'biphasic' response with a peak at leptin 10-9 M; a dose which is of physiological relevance in both mice and humans; returning to baseline with higher doses of leptin. This was true even in experiments conducted with C57BLIKs db/db mice, which lacked the membrane bound long leptin receptor (OB-Rb); thus highlighting the possible role of the membrane bound short leptin receptor (OBRa) in leptin induced visfatin protein production. Also, the apparent diminished response to higher doses of leptin with respect to visfatin production may be partly explained by the concurrent significant increase in the secretion of the soluble leptin receptor (SLR) at higher doses ofleptin. Binding ofleptin with SLR decreases the bioavailability of leptin to membrane bound leptin receptors and as a consequence, attenuates leptin's biological actions. Finally, when omental adipose tissues were subjected to leptin treatment in the presence of inhibitors of MAPK and PI3K, there was a significant decrease in leptin induced visfatin protein production and secretion. The MAPK and PI3K signalling pathways are known to functionally signal through both the short (OB-Ra) as well as the long (OB-Rb) leptin receptors. Leptin and visfatin may therefore playa coordinated role in various bodily functions, for example adipogenesis. Furthermore, the studies provide novel evidence that testosterone and 17~-estradiol increase both AdipoRl and AdipoR2 mRNA and protein levels; also, that 17~-estradiol significantly increases RBP4 secretion and up-regulates RBP4 mRNA expression and protein levels in human sc and om adipose tissue explants. Finally, HEK-293 cells were found to be suitable to further study and clarify the signalling pathways of both AdipoRl and AdipoR2. The temporal differences observed with respect to the activation ofAMPK between globular adiponectin and full length adiponectin forms the basis of further studies looking into the regulation of glucose and lipid metabolism, the molecular causes of diabetes and atherosclerosis, and the development of anti-diabetic and anti-atherosclerotic drugs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo