Hormone Regulation of NPY Neuron Activity in the Arcuate Nucleus of the Hypothalamus
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Neuropeptide Y (NPY)-expressing neurons in the arcuate nucleus of the hypothalamus are part of a neuroendocrine feedback loop that regulates feeding behavior and glucose homeostasis. NPY neurons sense peripheral signals of energy stores, including the hormones leptin, insulin, and ghrelin, and integrate those signals with inputs from other brain regions including serotonergic neurons from the dorsal raphe. These inputs modify both long-term changes in gene transcription and acute changes in the electrical activity of these neurons, leading to a coordinated response to maintain energy and glucose homeostasis. While the regulation of transcriptional changes in NPY neurons is relatively well-understood, the mechanisms by which insulin, leptin, ghrelin, and serotonin acutely modify the electrical activity of these neurons remains unclear. To determine ion channels that are coupled to hormone and neurotransmitter receptors present on NPY neurons, whole-cell patch clamp electrophysiology was performed on identified NPY neurons throughout the rostral-caudal extent of the arcuate nucleus of the hypothalamus. Leptin and insulin acutely hyperpolarized NPY neurons, and these effects were dependent upon opening of ATP-sensitive potassium (KATP) channels. In addition, serotonin and specific serotonin receptor-1b agonists acutely hyperpolarized NPY neurons. Conversely, the hormone ghrelin was found to acutely depolarize NPY neurons via a mixed cation conductance. Taken together, these studies demonstrate that at all levels of the arcuate nucleus, insulin, leptin, and serotonin acutely inhibit NPY neurons and that ghrelin acutely activates these neurons. Finally, a genetic model of NPY neuron-specific ablation of the intracellular phosphatidylinositol-3-kinase (PI3K) pathway was developed to assess the requirement of this cascade in mediating the acute effects of these hormones and the effects of NPY neurons on body weight and glucose homeostasis.