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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EProper function of the leptin\u2013melanocortin axis is important in regulating food intake and maintaining energy homeostasis. Therefore, mutations that affect the leptin\u2013melanocortin axis result in several known syndromes that result in an obesity phenotype. Recent research has further identified important components of this axis that may result in childhood-onset obesity as discussed in this article.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eobesity\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eobesity\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Epediatric nutrition\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eprevention \u0026amp; screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EProper function of the leptin\u2013melanocortin axis is important in regulating food intake and maintaining energy homeostasis. Therefore, mutations that affect the leptin\u2013melanocortin axis result in several known syndromes that result in an obesity phenotype. Recent research has further identified important components of this axis that may result in childhood-onset obesity.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EChristian Vaisse, MD, PhD, University of California San Francisco, San Francisco, California, USA, discussed the role of primary cilia function in pediatric obesity. Several syndromes caused by genetic aberrations can result in pediatric obesity, including the Bardet\u2013Biedl, Prader\u2013Willi, Alstrom, Borjeson\u2013Forssman\u2013Lehman, Cohen, and Carpenter syndromes. For Bardet\u2013Biedl syndrome, which can result in polydactyly, retinal degeneration, polycystic kidney disease, and obesity, \u0026gt; 12 genes have been identified, and these encode different proteins that play a role in the function of primary cilia.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EPrimary cilia are single, immotile sensory organelles that are present on multiple cell types, and their function is to transfer a variety of information from the extracellular environment to the cell. Ciliopathies have been implicated in a variety of disorders, including polycystic kidney disease, infertility, polydactyly, liver fibrosis, cerebellar defects, retinal degeneration, and heterotaxia. New data suggest that a ciliopathy may also result in obesity.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EIn animal models, ubiquitous impairment of primary cilia resulted in obesity. Furthermore, ablation of the primary cilia within differentiated neurons resulted in obesity in mice [Davenport JR et al. \u003Cem\u003ECurr Biol\u003C\/em\u003E 2007]. These data suggest that a receptor is required at the level of the primary cilium in differentiated neurons for long-term energy homeostasis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EIn the leptin\u2013melanocortin axis in the hypothalamus, leptin produced by adipocytes causes a signaling cascade that results in the activation of the melanocortin 4 receptor (MC4R) protein, which in turn signals to stop food intake. This pathway led to the hypothesis that primary cilia are important for MC4R function and that impaired MC4R function causes ciliopathies that result in obesity. \u003Cem\u003EIn vitro\u003C\/em\u003E data have demonstrated that all neurons that express MC4R also have primary cilia and that MC4R localizes to the primary cilia. In addition, an intracranial infusion of Melanotan (MT) II into mice resulted in decreased food intake. Primary cilia ablation resulted in body weight gain and impaired MC4R function. In human cells, the Pro78Leu, Pro230Leu, and Arg236Cys mutations in MC4R caused impaired cilia expression.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EDr. Vaisse concluded by highlighting the importance of MC4R expression for proper primary cilia function, and by stating that impaired cilia function, frequently caused by MC4R dysfunction, can result in obesity in animal models. Therefore, MC4R mutations in humans may cause a genetic predisposition for obesity.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EJoan C. Han, MD, National Institutes of Health, Bethesda, Maryland, USA, presented the role of brain-derived neurotropic factor (BDNF) in multiple forms of pediatric obesity. BDNF is a protein that is widely expressed in the nervous system and is important in the development of the nervous system during embryogenesis, as well as postnatal synaptic plasticity and neuronal survival [Pruunsild P et al. \u003Cem\u003EGenomics\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EBased on animal data, BDNF is downstream of the leptin\u2013proopiomelanocortin signaling pathway, in which activation of BDNF inhibits food intake [Wisse BE, Schwartz MW. \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2003]. In addition, haploinsufficiency of BDNF in mice results in hyperphagia and obesity. In humans, BDNF haploinsufficiency can cause an obesity subphenotype of WAGR syndrome, a rare disorder that is characterized by the classic clinical features of Wilms tumor, aniridia, genitourinary anomalies, and cognitive impairment. A subset of patients with WAGR syndrome also develop childhood-onset obesity. In patients with WAGR syndrome, the presence of BDNF haploinsufficiency is associated with higher body mass index (BMI) Z-score, childhood obesity, and hyperphagia [Han JC et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2008]. Analysis of the BDNF gene in patients with WAGR syndrome found that a deletion of the first 3 exons of BDNF is sufficient to cause the obesity subphenotype. In the general population, genome-wide association studies have consistently identified the BDNF gene locus as a region associated with obesity [Thorleifsson G et al. \u003Cem\u003ENat Genet\u003C\/em\u003E 2009], suggesting that BDNF insufficiency may have a role in common forms of obesity as well.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EApproaches for treating BDNF insufficiency focus on small-molecule agonists of the BDNF receptor, TrkB, or other mechanisms for increasing endogenous levels, because most peripherally administered BDNF does not cross the blood\u2013brain barrier; one such pharmacologic agent that shows promise is amitriptyline [Chadwick W et al. \u003Cem\u003EPLoS One\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EJoseph A. Majzoub, MD, Boston Children\u0027s Hospital, Boston, Massachusetts, USA, described the association of melanocortin receptor 2 accessory protein (MRAP2) and pediatric obesity. Recent advances in signaling pathways that regulate food intake have shed light on genetic causes of pediatric obesity. These pathways involve leptin, which ultimately regulates melanocortin 4 (MC4R), mutations that appear to result in impaired inhibition of food intake, thus resulting in increased food intake (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/20\/26\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Signaling Pathway That Affects Food Intake\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1726603503\u0022 data-figure-caption=\u0022Signaling Pathway That Affects Food Intake\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/20\/26\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/20\/26\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/20\/26\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/16442\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-12\u0022 class=\u0022first-child\u0022\u003ESignaling Pathway That Affects Food Intake\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced from O\u0027Rahilly S et al. Melanocortin receptors weigh in. \u003Cem\u003ENature Medicine\u003C\/em\u003E (2004). 10.4:351\u2013352. With permission from Nature Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EMRAP2 is an interacting partner of the MC4R receptor. Interestingly, mouse MRAP2 has recently been demonstrated to interact with MC4R \u003Cem\u003Ein vitro\u003C\/em\u003E, which appears to play a role in mammalian energy balance [Asai M et al. \u003Cem\u003EScience\u003C\/em\u003E 2013]. In addition, MRAP2 knockout mice have greater body weight that progressively increases throughout time compared with their wild-type and heterozygous counterparts, despite similar fecal energy output, energy expenditure, and locomotor activity. In obese humans, in MRAP2, located on chromosome 6, several amino acid\u2013changing mutations have been identified, including 1 in exon 2 and 1 in exon 4 [Asai M et al. \u003Cem\u003EScience\u003C\/em\u003E 2013]. Although further human studies are required, these data suggest that mutations in MRAP2 may play a role in obesity.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/20\/26.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzlw42\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlw42\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}