Faculty Bibliography

BACKGROUND:. At 3-year follow-up, surgery was very effective in T2D remission; furthermore, in the surgical group, those with a higher baseline soluble receptor for advanced glycation end products had a lower postoperative BMI. OBJECTIVES/OBJECTIVE:To provide long-term follow-up of this initial patient cohort. SETTING/METHODS:University Hospital. METHODS:Retrospective chart review was performed of the initial patient cohort. Patients lost to follow-up were systematically contacted to return to clinic for a follow-up visit. Data were compared using 2-sample t test, Fisher's exact test, or analysis of variance when applicable. RESULTS:; P = .007), and higher percent weight loss (21.4% versus 10.3%; P = .025). Baseline soluble receptor for advanced glycation end products was not associated with long-term outcomes. CONCLUSIONS:remains effective long term. Baseline soluble receptor for advanced glycation end products are most likely predictive of early outcomes only.

The role of advanced glycation end products (AGEs) in promoting and/or exacerbating metabolic dysregulation is being increasingly recognized. AGEs are formed when reducing sugars non-enzymatically bind to proteins or lipids, a process that is enhanced by hyperglycemic and hyperlipidemic environments characteristic of numerous metabolic disorders including obesity, diabetes and its complications. In this mini-review, we put forth the notion that AGEs span the spectrum from cause to consequence of insulin resistance (IR) and diabetes, and represent a "common soil" underlying the pathophysiology of these metabolic disorders. Collectively, the surveyed literature suggests that AGEs, both those that form endogenously as well as exogenous AGEs derived from environmental factors such as pollution, smoking and "Western" style diets, contribute to the pathogenesis of obesity and diabetes. Specifically, AGE accumulation in key metabolically-relevant organs induces IR, inflammation and oxidative stress, which in turn provide substrates for excess AGE formation, thus, creating a feed-forward fueled pathological loop mediating metabolic dysfunction.

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 ^-/-).

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

Macrophages accumulate prominently in the visceral adipose tissue (VAT) of obese humans and high fat diet (HFD) fed mice, and this is linked to insulin resistance and type II diabetes. While the mechanisms regulating macrophage recruitment in obesity have been delineated, the signals directing macrophage persistence in VAT are poorly understood. We previously showed that the neuroimmune guidance cue netrin-1 is expressed in the VAT of obese mice and humans, where it promotes macrophage accumulation. To better understand the source of netrin-1 and its effects on adipose tissue macrophage (ATM) fate and function in obesity, we generated mice with myeloid-specific deletion of netrin-1 (Ntn1^fl/flLysMCre^+/-; Ntn1^Δmac). Interestingly, Ntn1^Δmac mice showed a modest decrease in HFD-induced adiposity and adipocyte size, in the absence of changes in food intake or leptin, that was accompanied by an increase in markers of adipocyte beiging (Prdm16, UCP-1). Using single cell RNA-seq, combined with conventional histological and flow cytometry techniques, we show that myeloid-specific deletion of netrin-1 caused a 50% attrition of ATMs in HFD-fed mice, particularly of the resident macrophage subset, and altered the phenotype of residual ATMs to enhance lipid handling. Pseudotime analysis of single cell transcriptomes showed that in the absence of netrin-1, macrophages in the obese VAT underwent a phenotypic switch with the majority of ATMs activating a program of genes specialized in lipid handling, including fatty acid uptake and intracellular transport, lipid droplet formation and lipolysis, and regulation of lipid localization. Furthermore, Ntn1^Δmac macrophages had reduced expression of genes involved in arachidonic acid metabolism, and targeted LCMS/MS metabololipidomics analysis revealed decreases in proinflammatory eicosanoids (5-HETE, 6-trans LTB₄, TXB₂, PGD₂) in the obese VAT. Collectively, our data show that targeted deletion of netrin-1 in macrophages reprograms the ATM phenotype in obesity, leading to reduced adipose inflammation, and improved lipid handling and metabolic function.

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.

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.