This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The recently discovered hormone leptin is the primary signal of fat stores that is perceived by the brain. Leptin exerts negative feedback effects on energy intake and expenditure, and leptin insufficiency causes hyperphagia and decreased energy expenditure. Yet, little is known about how leptin acts on the brain to relay the signal of peripheral fat levels. One of the major targets of leptin is the proopiomelanocortin (POMC) neurons. These hypothalamic neurons secrete alpha-MSH, a neuropeptide that inhibits feeding and increases energy expenditure, and leptin directly increases the activity of these neurons, causing increased secretion of alpha-MSH. In previous studies we identified the mechanisms that leptin uses to acutely regulate POMC neurons. Another target of leptin is those hypothalamic neurons that secrete neuropeptide Y (NPY) and agouti related peptide (AGRP), neuropeptides that increase feeding and decrease energy expenditure. These different neurons can be visually identified by the targeted (transgenic) expression of 2 different colored fluorescent proteins. We propose to further characterize the actions of leptin on POMC neurons, and to extend these studies to the NPY neurons, by measuring their electrical activity in response to leptin treatment. We will determine how the leptin receptor can activate directly POMC neurons while directly inhibiting nearby NPY neurons by analyzing the intracellular signal transduction pathways used by leptin in each type of neuron, and the ion channels that are modulated in each class of neuron. A better understanding of these pathways is essential to develop therapies for obesity. We will evaluate how leptin affects these neurons in animals that have altered responses to leptin, to determine if these neurons play a role in the animals' physiological response to leptin. Finally, we will assess the response of these neurons to leptin and insulin in animals with diet-induced obesity and with a cachectic wasting syndrome, to determine if changes in the sensitivity of the POMC or NPY/AGRP neurons to signals of energy homeostasis contribute to these debilitating syndromes.
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