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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\u003EThe pandemic of metabolic disease caused by the increase in obesity is the greatest current threat to human health. At this time, 1.2 billion people worldwide are overweight or obese, and 400 million have been diagnosed with diabetes. This article discusses the integration of nutrients, immune response, and metabolism in health and disease.\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\u003Einflammatory disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EG\u00f6khan S. Hotamisligil, MD, PhD, Harvard School of Public Health, Boston, Massachusetts, USA, presented the Danone International Prize for Nutrition Laureate lecture on the integration of nutrients, immune response, and metabolism in health and disease. According to Dr. Hotamisligil, the pandemic of metabolic disease caused by the increase in obesity is the greatest current threat to human health. At this time, 1.2 billion people worldwide are overweight or obese, and 400 million have been diagnosed with diabetes [International Diabetes Federation. \u003Cem\u003EIDF Diabetes Atlas: Third Edition\u003C\/em\u003E, 2006. \u003Ca href=\u0022http:\/\/www.idf.org\/atlasmap\/atlasmap\u0022\u003Ehttp:\/\/www.idf.org\/atlasmap\/atlasmap\u003C\/a\u003E].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EIMMUNE RESPONSE AND METABOLIC DISEASE\u003C\/h2\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EIn 1943, Greene and Keohen suggested that infection was among the common causes of insulin resistance. Forty years later, Pekala, Cerami, and colleagues demonstrated that adipocytes develop insulin resistance when exposed to supernatants of endotoxin-treated macrophages. In addition, the researchers described the possible mechanism that involved defects in postreceptor insulin signaling [Pekala et al. \u003Cem\u003EJ Exp Med\u003C\/em\u003E 1983].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EIn 1993, Dr. Hotamisligil and colleagues found that inflammatory cytokines such as tumor necrosis factor alpha (TNF-a) are expressed in the white adipose tissue of obese mice. In 1995, two studies showed the same phenomenon in obese humans but not in lean individuals. Subsequent studies genetically linked TNF-a with insulin resistance and showed that TNF-a inhibition restored insulin function.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EDr. Hotamisligil and others have since shown that \u0026gt;50 cytokines, chemokines, and inflammatory mediators are associated with obesity and linked to insulin resistance and diabetes. Other studies have focused on the identification of key signaling molecules and triggering mechanisms to develop inhibiting therapies. Among these were studies showing that the c-Jun amino-terminal kinases (JNKs) are abnormally elevated and mediate insulin resistance and diabetes in obesity [Bluher M et al. \u003Cem\u003EJ Clin Endocrinol Met\u003C\/em\u003E 2009; Boden G et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2009; Hirosumi J et al. \u003Cem\u003ENature\u003C\/em\u003E 2002]. Numerous studies have shown that JNK activation in adipose tissue, muscle, macrophages, \u03b2 cells, and the brain impairs metabolism [Han MS et al. \u003Cem\u003EScience\u003C\/em\u003E 2013; Lanuza-Masdeu J et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2013; Henstridge DC et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2012; Zhang X \u003Cem\u003EDiabetes\u003C\/em\u003E 2011; Belgardt BF et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2010]. Additionally, pharmacologic JNK inhibition has been shown to promote metabolic homeostasis [Rondinone CM. \u003Cem\u003EExpert Opin Ther Targets\u003C\/em\u003E 2005; Kaneto H et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2004]. Other studies identified inhibitory kappa kinase, another central inflammatory signaling molecule as a key component of insulin resistance and diabetes [Yuan et al. \u003Cem\u003EScience\u003C\/em\u003E 2001]. Additional studies have shown that immune cells can infiltrate adipose tissue with obesity. Theses studies, as well as others, have shown that obesity and inflammation are linked.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe modified immune response that occurs with metabolic stress is referred to as \u003Cem\u003Emetabolic inflammation.\u003C\/em\u003E Also known as \u003Cem\u003Emetaflammation\u003C\/em\u003E, this response is characterized by signals and responses from metabolic cells such as adipocytes, interactions between metabolic and immune cells, and alterations in both energy management and insulin action (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). While inflammation is a critical adaptive response necessary for tissue repair and homeostasis, chronic inflammation is associated with some adverse events.\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\/5\/8\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Cellular Interactions in Metaflammation\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-847736740\u0022 data-figure-caption=\u0022Cellular Interactions in Metaflammation\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\/5\/8\/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\/5\/8\/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\/5\/8\/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\/16479\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-7\u0022 class=\u0022first-child\u0022\u003ECellular Interactions in Metaflammation\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from GS Hotamisligil, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EInflammation in adipose tissue involves macrophages, mast cells, T and B cells, and eosinophils. While adipose tissue is the most studied site of immune response in obesity, other tissues\u2014 such as liver, pancreas, and brain\u2014are part of these integrated pathways. Immunometabolism has emerged as new field of study that examines the role of chronic inflammation and stress in metabolic regulation, as well as the influence of metabolism on the immune response. According to Dr. Hotamisligil, immunometabolism has implications for a variety of chronic and metabolic diseases (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). Dr. Hotamisligil also stressed that the relation between immunity and metabolism is bidirectional. The immune response influences metabolic outcomes, but the metabolic milieu\u2014in immune cells and systemically\u2014also serves as a critical regulator of immune function.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\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\/5\/8\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Relationship Between Immunity and Metabolism\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-847736740\u0022 data-figure-caption=\u0022Relationship Between Immunity and Metabolism\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/5\/8\/F2.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\/5\/8\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\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\/5\/8\/F2.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\/16480\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 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-9\u0022 class=\u0022first-child\u0022\u003ERelationship Between Immunity and Metabolism\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from GS Hotamisligil, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EENDOPLASMIC RETICULUM STRESS AND DYSFUNCTION\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe endoplasmic reticulum (ER) is an intracellular organelle that is involved in protein synthesis, folding, trafficking, and quality control. The ER responds to changes in protein, lipid, and carbohydrate synthesis in the cell through 3 molecules in its membrane\u2014protein kinase RNA-like ER kinase, inositol-requiring enzyme 1 (IRE-1), and activating transcription factor 6 (ATF-6), which collectively maintain equilibrium in the ER. Obesity has been shown to disrupt this pathway, both in experimental models and in humans; however, weight loss can reverse this ER stress. The discovery that JNK is involved in activation of the IRE-1 pathway showed that JNK is closely linked to ER function, thereby stimulating further studies to explore the role of ER in obesity and diabetes [Urano et al. \u003Cem\u003EScience\u003C\/em\u003E 2002].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EChronic activation of ER due to stress and a defective response to proteins that have not yet been folded into the ER both play an important role in the development of insulin resistance and diabetes in obesity. Fu et al. [\u003Cem\u003EPLoS Genetics\u003C\/em\u003E 2012; \u003Cem\u003ECell Met\u003C\/em\u003E 2012; \u003Cem\u003ENature\u003C\/em\u003E 2011] studied the mechanisms leading to chronic ER stress in obesity. The researchers were able to clearly distinguish lean and obese ER proteomics and lipidomics. This study found increased lipogenesis, decreased protein and RNA synthesis, abnormal ER calcium homeostasis, mitochondrial defects, and altered bile acid metabolism associated with obesity. Alterations in autophagy and proteosome activity have also been found in association with obesity [Yang L et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2010]. These and other studies demonstrate that chronic excess energy and nutrients lead to abnormal ER morphology, organization, and function. It also has been shown that the ER can serve as a powerful recipient of nutrient and energy signals in the cells and that it is strongly influenced by the nutritional status of the organism.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EChronic inflammatory pathways are associated with the unfolded protein response, which is activated when the ER is stressed by the accumulation of newly synthesized unfolded proteins [Hotamisligil G. \u003Cem\u003ECell\u003C\/em\u003E 2010]. The inflammatory processes related to the unfolded protein response, molecular mediators, sensing mechanisms, and the related physiologic outcomes are not completely understood. However, under inflammatory conditions, defects in the expression of the unfolded protein response mediators ATF-6 and X-Box binding protein 1 have been identified in liver as well as in pancreatic \u03b2 cells from type 1 and type 2 diabetes (T1D and T2D) mouse models and humans [Engin F et al. \u003Cem\u003ESci Transl Med\u003C\/em\u003E 2013; \u003Cem\u003ESci Reports\u003C\/em\u003E 2013]. In T1D mice, restoration of the unfolded protein response in \u03b2 cells by administration of a chemical ER stress mitigator at the pre-diabetic stage resulted in a marked decrease in diabetes incidence, along with decreased pancreatic lymphocyte infiltration, improved \u03b2-cell survival and morphology, reduced \u03b2-cell apoptosis, preserved insulin secretion, and restored unfolded protein response mediator expression. Benefits of such interventions are also observed in T2D in experimental animal models and in humans [Kars et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2010; Xiao et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EDr. Hotamisligil stated that the molecular links between immune response and unfolded protein response are an area of intense study and that much remains to be discovered. The upstream signals that give rise to JNK activation and elF2a phosphorylation in obesity also are unclear. It is known that the elF2a kinase, a double-stranded RNA-dependent protein kinase, is activated in mouse and human obesity and plays a unique role in unfolded protein response and related inflammatory and metabolic events [Nakamura et al. \u003Cem\u003ECell\u003C\/em\u003E 2010; Carvalho-Filho et al. \u003Cem\u003EEndocrinology\u003C\/em\u003E 2012; Carvalho et al. \u003Cem\u003EObesity\u003C\/em\u003E 2013]. Double-stranded RNA-dependent protein kinases also coordinate the activity of JNK and other inflammatory kinases to regulate insulin action and metabolism [Nakamura T et al. \u003Cem\u003ECell\u003C\/em\u003E 2010]. Studies on this unique signaling molecule offer opportunities to understand which dietary and microbial components may directly engage immune pathways and allow mechanisms linking metabolism and immunity at the molecular level.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETARGETING METAFLAMMATION\u003C\/h2\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EAccording to Dr. Hotamisligil, many challenges lie ahead, but progress has been made in targeting metaflammation. TNF-a antagonism has been shown to decrease glucose levels and increase the proportion of high molecular weight adiponectin levels in obese humans with metabolic syndrome [Stanley TL et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2011]. Anti-TNF-a agents have reduced diabetes incidence by 50% in patients with rheumatoid arthritis and psoriasis in multiple studies [Solomon DH et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2011]. An interleukin-1 receptor antagonist also improved glycemia and \u03b2-cell function and reduced markers of systemic inflammation in patients with T2D in multiple independent studies [Larsen CM et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2007]. Glycemia also was improved by salsalate, a prodrug of salicylate, in patients with type 2 diabetes [Goldfine AB et al. \u003Cem\u003EAnn Intern Med\u003C\/em\u003E 2010]. While there are also unsuccessful attempts to utilize these agents in humans and it is yet unclear whether these specific drugs will find broad use in human disease, the field of immunometabolism is expanding faster than any other field, and more creative and effective strategies will surely be identified and applied to human disease.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EDr. Hotamisligil concluded that immunometabolic homeostasis is a delicate balance of forces, including host structure, genetic variation, environmental factors, physical activity, nutrient intake, stress, microbiota structure, circadian cycles, epigenetic effects, and the systemic energetics. Outcomes of health or disease depend on the interactions of these factors with the immune system. In immunometabolism, where multiple pathways are involved, it is unlikely that targeting a single aspect of the pathway will result in effective treatments. Rather, utilization of systematic approaches should teach us how best to modulate this response to promote health and prevent disease.\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\/5\/8.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?nzon6r\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?nzon6r\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}