Diabetes, leptin and the stress axis

Diabetes Mellitus is a chronic endocrine disease associated with a number of central and neuroendocrine dysfunctions due to lack of insulin, insulin action or both. A myriad of complications arise from the disease including retinopathy, nephropathy, neuropathy and cardiovascular dysfunction. Additionally, diabetes causes many neuroendocrine abnormalities including hyperphagia and polydypsia and hyperactivation of the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms, by which these neuroendocrine dysfunctions occur, however, are not known.; It has been shown that diabetes causes a significant increase in norepinephrine (NE) levels in the paraventricular nucleus (PVN) of the hypothalamus. Moreover, circulating leptin levels decrease significantly with the disease. The goal of the research comprised in this dissertation was to investigate whether this decrease in leptin could be one of the reasons for the central and neuroendocrine changes associated with the disease, including activation of the hypothalamo-pituitary-adrenal (HPA) axis.; The findings in this research suggest that leptin administration affects monoamine concentrations in the hypothalamus and serum corticosterone. Specifically, leptin administration was found to decrease NE concentration in the PVN and simultaneously decrease serum corticosterone. The dynamic changes in NE PVN and simultaneously decrease serum corticosterone. The dynamic changes in NE in the PVN due to leptin administration were assessed. It was found that peripheral leptin administration decreases noradrenergic activity in the PVN while simultaneously causing a decrease in HPA axis activity, as evidenced by decreased serum corticosterone. This effect was also observed in a subsequent study using a diabetic model, suggesting that leptin may play a modulatory role in the hyperactivation of the HPA axis seen in diabetes. The final experiment described in this dissertation shows that gene transfer using a lentiviral vector encoding leptin ( Ob) cDNA can ameliorate many of the neuroendocrine dysfunctions seen in diabetes including: hypoleptinemia, hypoinsulinemia, hyperglycemia, hyperphagia, polydipsia and diabetes-induced weight loss. Additionally gene transfer reduced the NE concentration in the PVN as well as serum corticosterone. Together these results suggest that leptin plays a modulatory role in many central and neuroendocrine actions and is likely involved in the neuroendocrine dysfunctions seen in diabetes.