Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin.

Ghamari-Langroudi M, Srisai D, Cone RD
Proc Natl Acad Sci U S A. 2011 108 (1): 355-60

PMID: 21169216 · PMCID: PMC3017160 · DOI:10.1073/pnas.1016785108

Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.

MeSH Terms (20)

alpha-MSH Animals Arcuate Nucleus of Hypothalamus Electrophysiology Energy Metabolism Green Fluorescent Proteins Homeostasis Immunohistochemistry Leptin Melanocortins Mice Mice, Inbred C57BL Mice, Transgenic Models, Neurological Neurons Neuropeptide Y Paraventricular Hypothalamic Nucleus Polymerase Chain Reaction Receptor, Melanocortin, Type 4 Signal Transduction

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