Faculty Bibliography

Objectives Brown adipose tissue (BAT) is responsible for adaptive thermogenesis and energy expenditure, its activity is mediated by mitochondrial uncoupling protein 1 which leads to the heat production by uncoupling electron transport chain. It is known that the genetic deficiency of RAGE (receptor for advanced glycation end products) can prevent the effects of high-fat diet (HFD) on energy expenditure, obesity, adipose tissue inflammation, and insulin resistance.1-2 Thus, the aim of this study was to compare the BAT activity3 in RAGE null and wild type (WT) mice in response to different diet conditions. Methods PET/CT imaging (Siemens, Inveon) of 4 groups of male C57/BL6 mice were compared (Ager ^-/--LFD, Ager ^-/--HFD, WT-LFD and WT-HFD). Before each scan, all mice were fasted for at least 4 h and then exposed to a cold-pack (0- 4degreeC) for 30 min. For each study, a dynamic PET scan was carried out for 1 h, followed by a CT scan (6 min) for the purpose of attenuation correction and co-registration. SUVmean (mean standard uptake values), SUVR (ratio of SUViBAT/SUVmuscle), and %ID/g for the interscapular BAT were determined. Results Preliminary results are summarized here: 1) For LFD mice, the uptake was significantly higher in WT-LFD (SUVR: 4.03+/-0.4) than that in Ager ^-/--LFD (SUVR: 1.4+/-0.1); 2) The SUVR were similar for both WT-HFD and Ager ^-/--HFD (1.4+/-0.1 and 1.52+/-0.1, respectively) (Figure 1); 3) Among Ager ^-/- types, the uptake was similar in both Ager ^-/--HFD (SUVR: 1.52+/-0.1) and Ager ^-/--LFD (SUVR: 2.14+/-0.1), and the %ID/g values were similar in both as well. These findings corroborate our previous findings on Ucp1-mRNA2; that is, (1) Ucp1-mRNA transcripts in BAT are almost halved in Ager ^-/--LFD than in WTLFD; (2) in HFD, Ucp1-mRNA transcripts did not differ in BAT between WT and Ager ^-/- mice; (3) a bigger change was observed in Ucp1-mRNA between WT-LFD and WT-HFD, while a smaller change was seen between Ager ^-/--LFD and Ager ^-/- -HFD. Conclusions In WT mice, BAT activity was significantly reduced after HFD as compared to LFD; however, BAT activity was not affected by HFD in Ager ^-/- mice. The consistent findings between the current in vivo PET imaging study of BAT and our previous study of Ucp1-mRNA further support our hypothesis that RAGE may contribute to altered energy expenditure, and provide a protective effect against HFD by Ager deletion. (Figure presented)

The receptor for advanced glycation endproducts (RAGE) interacts with a unique repertoire of ligands that form and collect in the tissues and circulation in diabetes mellitus, aging, inflammation, renal failure, and obesity. RAGE is expressed on multiple cell types linked to tissue perturbation in these settings. This brief review focuses on the role of RAGE in monocytes/macrophages and how RAGE ligand engagement on these cells mediates seminal changes in monocyte/macrophage migration, oxidative stress, cholesterol efflux, and pro- versus anti-inflammatory cues that signal to tissue damage. Studies using mice devoid of Ager (gene encoding RAGE) or pharmacological antagonists of RAGE are protective in animal models of diabetes mellitus, atherosclerosis, and high-fat diet-induced obesity, in least in part through key roles in monocytes/macrophages. RAGE signal transduction requires the interaction of RAGE cytoplasmic domain with the formin, DIAPH1 and novel antagonists of this interaction show significant promise in attenuation of the maladaptive effects of RAGE ligands in cellular and in vivo models. Finally, this brief review discusses evidence for RAGE axis perturbation in human monocytes/macrophages and how tracing RAGE activity in these cells may identify target engagement biomarkers of RAGE antagonism for future clinical trials.

The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and danger-associated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. Acinetobacter baumannii is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of A. baumannii pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE-/- mice systemically infected with A. baumannii exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE-/- mice is associated with increased circulating levels of the anti-inflammatory cytokine, IL-10. Neutralization of IL-10 in RAGE-/- mice results in decreased survival during systemic A. baumannii infection that mirrors that of WT mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis.

INTRODUCTION: The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

The process of advanced glycation leads to the generation and accumulation of an heterogeneous class of molecules called advanced glycation endproducts, or AGEs. AGEs are produced to accelerated degrees in disorders such as diabetes, renal failure, inflammation, neurodegeneration, and in aging. Further, AGEs are present in foods and in tobacco products. Hence, through both endogenous production and exogenous consumption, AGEs perturb vascular homeostasis by a number of means; in the first case, AGEs can cause cross-linking of long-lived molecules in the basement membranes such as collagens, thereby leading to "vascular stiffening" and processes that lead to hyperpermeability and loss of structural integrity. Second, AGEs interaction with their major cell surface signal transduction receptor for AGE or RAGE sets off a cascade of events leading to modulation of gene expression and loss of vascular and tissue homeostasis, processes that contribute to cardiovascular disease. In addition, it has been shown that an enzyme, which plays key roles in the detoxification of pre-AGE species, glyoxalase 1 (GLO1), is reduced in aged and diabetic tissues. In the diabetic kidney devoid of Ager (gene encoding RAGE), higher levels of Glo1 mRNA and GLO1 protein and activity were observed, suggesting that in conditions of high AGE accumulation, natural defenses may be mitigated, at least in part through RAGE. AGEs are a marker of arterial aging and may be detected by both biochemical means, as well as measurement of "skin autofluorescence." In this review, we will detail the pathobiology of the AGE-RAGE axis and the consequences of its activation in the vasculature and conclude with potential avenues for therapeutic interruption of the AGE-RAGE ligand-RAGE pathways as means to forestall the deleterious consequences of AGE accumulation and signaling via RAGE.

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)>/=97pg/mL, CRP>/=2.4mg/L, and MMP-9