HYPOTHALAMIC NEUROPEPTIDE PATHWAYS MEDIATING SYMPATHETIC RESPONSES TO LEPTIN

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Circulating leptin produced by adipocytes influences feeding behavior and metabolic processes through its effects on the central nervous system. Recent studies have implicated hypothalamic neuropeptide Y (NPY), corticotrophin releasing factor (CRF) and the melanocortins in these processes. Our preliminary data indicate that leptin increases sympathetic nerve activity (SNA) to intrascapular brown adipose tissue (IBAT), adrenal gland (Adr), kidney, and skeletal muscle. Leptin affects feeding behavior via its receptors (OB-Rb) in the hypothalamus, which is also an important site driving the sympathetic nervous system. However, the mechanisms by which leptin initiates sympathetic excitation have not been determined. The Orexigenic peptide NPY inhibits IBAT SNA when microinjected into the paraventricular nucleus (PVN) of hypothalamus and thus may modulate the activity of sympathoexcitatory PVN neurons. We hypothesize that the excitation of these neurons is mediated by alpha melanocyte stimulating hormone (alpha-MSH), acting on the MC4-R receptors have recently been found to suppress feeding behavior, and that leptin permits this excitation by its known effect of reducing hypothalamic NPY and NPY release in PVN. We also hypothesize that leptin induced sympathoexcitation is mediated, at least in part, by CRF-containing PVN neurons projecting to brain stem and spinal cord. Three neural control laboratories will collaborate in testing these hypotheses. Dr. Mark's lab will test the effect of circulating leptin on IBAT, Adr and renal SNA after discrete hypothalamic lesions and regional microinjections of peptides (alpha-MSH and NPY) and peptide antagonists into critical hypothalamic subnuclei. Dr. Felder's lab will test the effects of NPY and alpha-MSH on single PVN neurons, and their role in mediating PVN neuronal responses to leptin infusion. Dr. Johnson's lab will use immunohistochemical and microinjection techniques to determine the role of descending CRF- containing PVN neurons in mediating the responses to intravenous leptin. These studies will provide important new insights into the link between leptin, a humoral signal generated in adipose tissue, and activation of autonomic mechanisms regulating peripheral metabolic function.