Date of Award
Doctor of Philosophy (PhD)
Obesity, a recognized health problem, is associated with cardiovascular disease, diabetes and hypertension. Removal of adrenal steroids by adrenalectomy (ADX) slows the development of obesity. Leptin decreases food intake through effects initiated by activation of the JAK-STAT pathway. Defects in leptin signaling lead to obesity, which is associated with hyperleptinemia and leptin resistance. In chapter 4, leptin induces phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and increases glucose production in hepatocytes from lean but not obese Zucker rats. This suggests that hyperleptinemia in obesity causes hyperglycemia. In chapter 5, ADX decreased the levels of PEPCK mRNA, and increased leptin receptor mRNA expression of obese Zucker rats. The decrease in PEPCK mRNA is presumed to correct the hyperglycemia in these rats. ADX decreases leptin levels and increases leptin receptor (OBR) mRNA in obese Zucker rats, suggesting that leptin downregulates OBR. ADX was reported to increase sensitivity to leptin treatment. I hypothesized that high glucocorticoids in obesity impaired OBR signaling, and removal thereof will activate this pathway. In chapter 6, ADX increased the expression of leptin receptor mRNA in Sprague Dawley rats. ADX increased STAT-3 mRNA and protein levels, and induced constitutive STAT-3 phosphorylation and DNA binding activity. ADX also reduced SOCS-3 mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. We speculate that PIAS-3, a protein inhibitor of activated STAT-3, inhibited DNA binding of the activated STAT-3 as a protective measure of cytokine hypersensitivity in the absence of SOCS-3. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. In conclusion, ADX mimicked leptin in activating STAT-3, and ADX decreased SOCS-3 inhibitory system. Leptin sensitivity could also result from the release of anorexigenic and orexigenic neuropeptides, but more research is warranted. In chapter 7, high-fat diet induced leptin resistance could be due to downregulation of the leptin receptor proteins in the hypothalamus. Further research is required to define the leptin resistance in OM rats induced by high fat diet, such as changes in leptin receptor signaling and SOCS-3 expression.
Madiehe, Abram Madimabe, "Glucocorticoid Regulation of the Leptin Receptor Signaling System in the Rat." (2000). LSU Historical Dissertations and Theses. 7375.