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      The Melanin-Concentrating Hormone as an Integrative Peptide Driving Motivated Behaviors

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          Abstract

          The melanin-concentrating hormone (MCH) is an important peptide implicated in the control of motivated behaviors. History, however, made this peptide first known for its participation in the control of skin pigmentation, from which its name derives. In addition to this peripheral role, MCH is strongly implicated in motivated behaviors, such as feeding, drinking, mating and, more recently, maternal behavior. It is suggested that MCH acts as an integrative peptide, converging sensory information and contributing to a general arousal of the organism. In this review, we will discuss the various aspects of energy homeostasis to which MCH has been associated to, focusing on the different inputs that feed the MCH peptidergic system with information regarding the homeostatic status of the organism and the exogenous sensory information that drives this system, as well as the outputs that allow MCH to act over a wide range of homeostatic and behavioral controls, highlighting the available morphological and hodological aspects that underlie these integrative actions. Besides the well-described role of MCH in feeding behavior, a prime example of hypothalamic-mediated integration, we will also examine those functions in which the participation of MCH has not yet been extensively characterized, including sexual, maternal, and defensive behaviors. We also evaluated the available data on the distribution of MCH and its function in the context of animals in their natural environment. Finally, we briefly comment on the evidence for MCH acting as a coordinator between different modalities of motivated behaviors, highlighting the most pressing open questions that are open for investigations and that could provide us with important insights about hypothalamic-dependent homeostatic integration.

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          Loss of recent memory after bilateral hippocampal lesions.

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            Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

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              Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity.

              A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
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                Author and article information

                Contributors
                Journal
                Front Syst Neurosci
                Front Syst Neurosci
                Front. Syst. Neurosci.
                Frontiers in Systems Neuroscience
                Frontiers Media S.A.
                1662-5137
                29 May 2017
                2017
                : 11
                : 32
                Affiliations
                [1] 1Laboratory of Chemical Neuroanatomy, Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo São Paulo, Brazil
                [2] 2Center for Neuroscience and Behavior, Institute of Psychology, University of São Paulo São Paulo, Brazil
                Author notes

                Edited by: Joel D. Hahn, University of Southern California, United States

                Reviewed by: Scott E. Kanoski, University of Southern California, United States; Jessica R. Barson, Drexel University College of Medicine, United States

                *Correspondence: Jackson C. Bittencourt, jcbitten@ 123456icb.usp.br
                Article
                10.3389/fnsys.2017.00032
                5447028
                28611599
                ddb58ce8-e55a-4ccf-b320-0fd1adee288e
                Copyright © 2017 Diniz and Bittencourt.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 February 2017
                : 04 May 2017
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 293, Pages: 26, Words: 0
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Award ID: 2016/02748-0
                Award ID: 2010/52068-0
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 10.13039/501100002322
                Award ID: 848/15
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Categories
                Neuroscience
                Review

                Neurosciences
                mch,hypothalamus,energy homeostasis,feeding behavior,reward,foraging,metabolism
                Neurosciences
                mch, hypothalamus, energy homeostasis, feeding behavior, reward, foraging, metabolism

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