Obesity is a common and costly health issue that arises in part from defects in physiological mechanisms regulating energy homeostasis. Recent evidence indicates that obesity is associated with a reduced ability of the adiposity hormones insulin and leptin to engage key neuronal circuits within the brain, and that genetic modifications that enhance insulin and leptin sensitivity protect against the development of diet-induced obesity. This data thus indicates that alterations in leptin and insulin sensitivity likely contribute to the development of obesity. This proposal describes a series of experiments which attempt to define key brain regions that are necessary for leptin action, and determine whether high fat feeding induces alterations in common signaling pathways that promote leptin and insulin resistance within these areas. Specifically, we propose to determine whether the physiological response to increased circulating leptin requires concerted or independent contributions from the forebrain and hindbrain. Published data clearly indicates that leptin is capable of acting in either the forebrain (hypothalamus) or hindbrain to regulate feeding behavior. However, the relative importance of these 2 areas in sensing changes in circulating leptin is poorly characterized. To test this hypothesis, we propose to use a variety of pharmacological tools to selectively impair leptin signaling within either the forebrain or hindbrain, and determine if this loss of signaling alters the response to physiologic increases in circulating leptin. In addition to defining key brain areas mediating leptin action, we also propose to determine whether diet-induced obesity induces insulin and leptin resistance locally within these areas, and whether increases in protein tyrosine phosphatase 1B (PTP1B) provide a molecular mechanism for this common insulin and leptin resistance. Biochemical and genetic data indicate that PTP1B selectively inhibits both leptin and insulin signaling, and our preliminary data indicates that PTP1B is elevated within the hypothalamus of leptin resistant rats. We propose to extend this work by testing whether consumption of a high fat diet is associated within increases in PTP1B activity within either the hypothalamus or brainstem. In addition, we will also determine whether PTP1B signaling within these brain areas is necessary for leptin and insulin resistance by testing whether acute inhibition of PTP1B restores leptin and insulin dependent signaling within these areas. We propose that defects in the activation of common signaling pathways underlie the insensitivity to leptin and insulin characteristic of obesity. Therefore, a clear understanding of the cellular signaling events impacting both insulin and leptin signaling within brain areas necessary for their action is of significant scientific and clinical importance. ? ? ?
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