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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\u003EThis article summarizes a body of work investigating the pathways and relationships between obesity, inflammation, insulin resistance, and heart failure.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease Heart Failure\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHeart Failure\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EIppei Shimizu MD, PhD, Boston University School of Medicine, Boston, Massachusetts, USA, summarized a body of work investigating the pathways and relationships between obesity, inflammation, insulin resistance, and heart failure.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003Ep53 is an important tumor suppressor protein involved in DNA repair, apoptosis, and cell cycle regulation. Earlier work demonstrated that p53 in adipose tissue regulates systemic insulin resistance in obesity [Minamino T et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2009]. Additionally, in mice that underwent thoracic aortic constriction (TAC; a model for heart failure), an increase in p53 expression, systemic insulin resistance, and adipose tissue inflammation was observed. When TAC was performed on p53 knockout mice, reduced adipose tissue inflammation and insulin resistance were observed. This and additional experiments led to the conclusion that heart failure upregulates p53 in adipose tissue, which in turn leads to inflammation of adipose tissue and systemic insulin resistance [Shimizu I et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EWhen the heart is overloaded, cardiac hypertrophy results, ultimately leading to heart failure if the overload is sustained. Cardiac angiogenesis can prevent the progression to heart failure and, conversely, cardiac function worsens when cardiac angiogenesis is inhibited. Dr. Shimizu believes that basal cardiac insulin signaling is critical in maintaining cardiac homeostasis; however, when TAC was performed in mice with deleted cardiac insulin receptors, cardiac function was improved and less hypertrophy was observed. This result suggested that excessive cardiac insulin signaling may induce cardiac hypertrophy and deteriorate cardiac function during pressure-overload [Shimizu I et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2010]. In summarizing their overall findings from multiple experiments, Dr. Shimizu said that heart failure upregulates sympathetic activity and lipolysis, leading to increased adipose tissue p53 levels. This in turn results in systemic insulin resistance that exacerbates heart failure.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn terms of potential therapies, it is unlikely that p53 itself is a viable therapeutic target. \u201cp53 is the \u2018guardian of the genome\u2019 and inhibition of this molecule is problematic because it promotes cancer. It is critically important to find a molecule located downstream of p53,\u201d said Dr. Shimizu. Semaphorin 3E and its receptor Plexin-D1 (Sema3E\/PlexinD1) may be a potential therapeutic pathway. Semaphorin-plexin signaling regulates immune cell function and both are involved in vessel formation, but their association with obesity is currently unknown.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EDr. Shimizu shared some recent data regarding his Sema3E\/PlexinD1 research. A murine obese model was created by giving mice a high-fat, high-sucrose diet. This led to diet-induced obesity with associated adipose inflammation and impaired glucose metabolism. Significant increases in both the circulating level of Sema3E and expression in adipose tissue were observed in these mice. The PlexinD1 level also was also increased in the obese adipose tissue, primarily in macrophages. Results from a migration assay indicated that Sema3E functions as a chemo-attractant for macrophages, and that this chemo-attractant activity is plexinD1 dependent. In his concluding remarks, Dr. Shimizu said he believes that their data suggest that the inhibition of the Sema3E\/PlexinD1 pathway is a potential treatment target in adipose inflammation and metabolic dysfunction in obesity.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 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\/13\/11\/33.1.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_openurl.js?nznrpd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}