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      Action of Neurotransmitter: A Key to Unlock the AgRP Neuron Feeding Circuit

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          The current obesity epidemic and lack of efficient therapeutics demand a clear understanding of the mechanism underlying body weight regulation. Despite intensive research focus on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. Exciting studies in last decades have established the importance of hypothalamic agouti-related protein-expressing neurons (AgRP neurons) in the regulation of body weight homeostasis. AgRP neurons are both required and sufficient for feeding regulation. The activity of AgRP neurons is intricately regulated by nutritional hormones as well as synaptic inputs from upstream neurons. Changes in AgRP neuron activity lead to alterations in the release of mediators, including neuropeptides Neuropeptide Y (NPY) and AgRP, and fast-acting neurotransmitter GABA. Recent studies based on mouse genetics, novel optogenetics, and designer receptor exclusively activated by designer drugs have identified a critical role for GABA release from AgRP neurons in the parabrachial nucleus and paraventricular hypothalamus in feeding control. This review will summarize recent findings about AgRP neuron-mediated control of feeding circuits with a focus on the role of neurotransmitters. Given the limited knowledge on feeding regulation, understanding the action of neurotransmitters may be a key to unlock neurocircuitry that governs feeding.

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          Most cited references 105

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          The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
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            We have produced a mouse strain in which the deletion of the NMDAR1 gene is restricted to the CA1 pyramidal cells of the hippocampus by using a new and general method that allows CA1-restricted gene knockout. The mutant mice grow into adulthood without obvious abnormalities. Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning. Our results strongly suggest that activity-dependent modifications of CA1 synapses, mediated by NMDA receptors, play an essential role in the acquisition of spatial memories.
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              Anatomy and regulation of the central melanocortin system.

               R D Cone (2005)
              The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.

                Author and article information

                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                21 January 2013
                : 6
                1Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas Dallas, TX, USA
                2The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston Houston, TX, USA
                Author notes

                Edited by: Kevin W. Williams, The University of Texas Southwestern Medical Center, USA

                Reviewed by: Serge H. Luquet, University Paris Diderot-Paris 7, France; Scott Sternson, Howard Hughes Medical Institute, USA; Qi Wu, University of Iowa, USA

                *Correspondence: Qingchun Tong, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, TX 77030, USA. e-mail: qingchun.tong@ 123456uth.tmc.edu

                This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Neuroscience.

                Copyright © 2013 Liu, Wang, Berglund and Tong.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 130, Pages: 9, Words: 9520
                Review Article


                agrp neurons, feeding, parabrachial nucleus, paraventricular hypothalamus


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