This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Melanocortin neurons are regulated by leptin and glucose, and other signals of nutritional state. These signals reach the neurons because of a leaky blood brain barrier at the median eminence. In obesity, it appears that leptin no longer regulates the melanocortin system. We are testing the hypothesis that leptin is excluded from the brain because the blood brain barrier changes, and becomes less permeable at the median eminence of obese mice. We are also testing to determine if obesity causes a loss of glucose sensing in melanocortin neurons, and if this loss of glucose sensing causes changes in systemic glucose homeostasis. Specifically we have been testing if obesity-induced melanocortin resistance to glucose releases the liver from a tonic inhibition, and allows the liver to secrete more glucose, requiring more insulin to control blood glucose levels in a normal range. We are testing this hypothesis in obese glucose intolerant mice. Both of these hypotheses have the potential to generate new therapeutic strategies to treat obesity and early Type II diabetes.
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