Faculty Bibliography

Brown adipose tissue (BAT) is responsible for adaptive thermogenesis. We previously showed that genetic deficiency of receptor for advanced glycation end products (RAGE) prevented the effects of high-fat diet (HFD). This study was to compare BAT activity in RAGE knock out (Ager^-/-, RKO) and wild-type (WT) mice after treated with HFD or LFD. [¹⁸F]FDG PET-CT imaging under identical cold-stimulated conditions and mean standard uptake values (SUV_mean), ratio of SUV_iBAT/SUV_muscle (SUVR, muscle as the reference region) and percentage ID/g were used for BAT quantification. The results showed that [¹⁸F]FDG uptake (e.g., SUVR) in WT-HFD mice was significantly reduced (three-fold) as compared to that in WT-LFD (1.40 +/- 0.07 and 4.03 +/- 0.38; P = 0.004). In contrast, BAT activity in RKO mice was not significantly affected by HFD, with SUVR_RKO-LFD: 2.14 +/- 0.10 and SUVR_RKO-LFD: 1.52 +/- 0.13 (P = 0.3). The uptake in WT-LFD was almost double of that in RKO-LFD (P = 0.004); however, there was no significant difference between RKO-HFD and WT-HFD mice (P = 0.3). These results, corroborating our previous findings on the measurement of mRNA transcripts for UCP1 in the BAT, suggest that RAGE may contribute to altered energy expenditure and provide a protective effect against HFD by Ager deletion (Ager ^-/-).

Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation-processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.

Incense burning is common worldwide and produces environmental toxicants that may influence health; however, biologic effects have been little studied. In 303 Emirati adults, we tested the hypothesis that incense use is linked to compositional changes in the oral microbiota that can be potentially significant for health. The oral microbiota was assessed by amplification of the bacterial 16S rRNA gene from mouthwash samples. Frequency of incense use was ascertained through a questionnaire and examined in relation to overall oral microbiota composition (PERMANOVA analysis), and to specific taxon abundances, by negative binomial generalized linear models. We found that exposure to incense burning was associated with higher microbial diversity (p < 0.013) and overall microbial compositional changes (PERMANOVA, p = 0.003). Our study also revealed that incense use was associated with significant changes in bacterial abundances (i.e. depletion of the dominant taxon Streptococcus), even in occasional users (once/week or less) implying that incense use impacts the oral microbiota even at low exposure levels. In summary, this first study suggests that incense burning alters the oral microbiota, potentially serving as an early biomarker of incense-related toxicities and related health consequences. Although a common indoor air pollutant, guidelines for control of incense use have yet to be developed.

Background/UNASSIGNED:(the gene encoding RAGE), have been reported to be associated with T2D and its complications, we tested for potential relationships between these factors and T2D status in Emirati subjects. Methods/UNASSIGNED:In a case-control study, we recruited Emirati subjects with T2D and controls from the Sheikh Khalifa Medical City in Abu Dhabi. Anthropomorphic characteristics, levels of plasma sRAGE and esRAGE, and routine chemistry variables were measured. Results/UNASSIGNED: = 0.01, after adjustment for age and sex). Conclusion/discussion/UNASSIGNED:Levels of sRAGE, but not esRAGE, were associated with T2D status in Abu Dhabi, but not after correction for eGFR. Elevated levels of plasma insulin in both control and T2D subjects suggests the presence of metabolic dysfunction, even in subjects without diabetes.

Macrophages play an essential role in regression of diabetic atherosclerosis. A key player in these processes is Receptor for Advanced Glycation End Products (RAGE), which binds specific ligands enriched in atherosclerotic plaques. Here, we sought to test the mechanisms by which deletion of Ager in diabetic mice accelerates regression of atherosclerosis in an aorta transplantation model in which donor aortic arches from diabetic Ldlr null Western diet-fed mice (CD45.2) are transplanted into diabetic wild-type (WT) or homozygous Ager null mice (CD45.1), thereby effecting lipid lowering and promoting regression, which was improved in Ager null vs. WT mice. We employed RNA sequencing to identify the transcriptional events by which RAGE mediates its effects in donor (CD45.2) and/or recipient (CD45.1) macrophages in diabetic regressing plaques. Our results suggest that critical gene expression profiles, including those genes involved in interferon signaling, particularly the gene encoding interferon regulating factor-7 (Irf7), monocyte/macrophage fate (recruitment, proliferation, apoptosis), and lipid metabolism, are beneficially modulated, at least in part, via Ager deletion particularly in the recipient CD45.1 macrophages in atherosclerosis regression. We tested the role of the IRF7 pathway and our findings, to date, include: 1) There is a decrease in IRF7+/ macrophage area in plaques retrieved from diabetic Ager null vs. diabetic WT mice; 2) Levels of IFN-gamma are lower in diabetic Ager null vs. WT diabetic recipient mice after transplantation; 3) Bone marrow derived macrophages (BMDMs) treated with 2% serum from Ldlr null mice fed Western diet resulted in significant upregulation of Irf7 in WT but not in Ager null BMDMs; and 4) Upon treatment with 2% serum from Ldlr mice fed Western diet, significant upregulation of genes involved in cholesterol transport (Abca1 and Abcg1) was only observed in Ager null but not WT BMDMs compared to treatment with serum from WT normolipidemic mice. These findings suggest that RAGE may affect lipid driven regulation of the interferon-signaling pathway to impair regression of diabetic atherosclerosis. These data may provide avenues for therapeutic strategies to accelerate regression of diabetic atherosclerosis

The Receptor for Advanced Glycation End Products (RAGE) is expressed by multiple cell types in the brain and spinal cord that are linked to the pathogenesis of neurovascular and neurodegenerative disorders, including neurons, glia (microglia and astrocytes) and vascular cells (endothelial cells, smooth muscle cells and pericytes). Mounting structural and functional evidence implicates the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous1 (DIAPH1), as the key cytoplasmic hub for RAGE ligand-mediated activation of cellular signaling. In aging and diabetes, the ligands of the receptor abound, both in the central nervous system (CNS) and in the periphery. Such accumulation of RAGE ligands triggers multiple downstream events, including upregulation of RAGE itself. Once set in motion, cell intrinsic and cell-cell communication mechanisms, at least in part via RAGE, trigger dysfunction in the CNS. A key outcome of endothelial dysfunction is reduction in cerebral blood flow and increased permeability of the blood brain barrier, conditions that facilitate entry of activated leukocytes into the CNS, thereby amplifying primary nodes of CNS cellular stress. This contribution details a review of the ligands of RAGE, the mechanisms and consequences of RAGE signal transduction, and cites multiple examples of published work in which RAGE contributes to the pathogenesis of neurovascular perturbation. Insights into potential therapeutic modalities targeting the RAGE signal transduction axis for disorders of CNS vascular dysfunction and neurodegeneration are also discussed.

Weight loss reduces the risk of type 2 diabetes mellitus (T2D) in overweight and obese individuals. Although the physiological response to food varies among individuals, standard dietary interventions use a "one-size-fits-all" approach. The Personal Diet Study aims to evaluate two dietary interventions targeting weight loss in people with prediabetes and T2D: (1) a low-fat diet, and (2) a personalized diet using a machine-learning algorithm that predicts glycemic response to meals. Changes in body weight, body composition, and resting energy expenditure will be compared over a 6-month intervention period and a subsequent 6-month observation period intended to assess maintenance effects. The behavioral intervention is delivered via mobile health technology using the Social Cognitive Theory. Here, we describe the design, interventions, and methods used.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage^-/- mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients.