Try a new search

Format these results:

Searched for:



Total Results:


The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease

Arivazhagan, Lakshmi; Popp, Collin J; Ruiz, Henry H; Wilson, Robin A; Manigrasso, Michaele B; Shekhtman, Alexander; Ramasamy, Ravichandran; Sevick, Mary Ann; Schmidt, Ann Marie
Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond endogenous formation of advanced glycation end products (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production and consumption of highly-processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signaling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.
PMID: 36448548
ISSN: 1755-3245
CID: 5383622

Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice

Wilson, Robin A; Arivazhagan, Lakshmi; Ruiz, Henry H; Zhou, Boyan; Qian, Kun; Manigrasso, Michaele B; Bernadin, Rollanda; Mangar, Kaamashri; Shekhtman, Alexander; Li, Huilin; Ramasamy, Ravichandran; Schmidt, Ann Marie
OBJECTIVE:Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global- or adipocyte-specific deletion of Ager (the gene encoding RAGE) protected mice from high-fat diet-induced obesity and metabolic dysfunction. METHODS:To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet-induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. RESULTS:This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. CONCLUSIONS:Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.
PMID: 37231626
ISSN: 1930-739x
CID: 5539822

AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity

Ruiz, Henry H; Nguyen, Anh; Wang, Chan; He, Linchen; Li, Huilin; Hallowell, Peter; McNamara, Coleen; Schmidt, Ann Marie
BACKGROUND/OBJECTIVES/OBJECTIVE:The incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by "Westernization" of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be "trapped" in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences. SUBJECTS/METHODS/METHODS:We sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects. RESULTS:In SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; [Formula: see text], [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; [Formula: see text], [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; [Formula: see text], [0.338, 1.249]; q = 0.018). CONCLUSIONS:These observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.
PMID: 34103691
ISSN: 1476-5497
CID: 4903152

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

MacLean, Michael; Juranek, Judyta; Cuddapah, Swetha; López-Díez, Raquel; Ruiz, Henry H; Hu, Jiyuan; Frye, Laura; Li, Huilin; Gugger, Paul F; Schmidt, Ann Marie
BACKGROUND:Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. METHODS:mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. RESULTS:mice. CONCLUSIONS:murine pathology in male mice and may be relevant in human disease.
PMID: 34130712
ISSN: 1742-2094
CID: 4903542

Central Regulation of Branched-Chain Amino Acids Is Mediated by AgRP Neurons

Gannaban, Ritchel B; NamKoong, Cherl; Ruiz, Henry H; Choi, Hyung Jin; Shin, Andrew C
Circulating branched-chain amino acids (BCAAs) are elevated in obesity and diabetes, and recent studies support a causal role for BCAAs in insulin resistance and defective glycemic control. The physiological mechanisms underlying BCAA regulation are poorly understood. Here we show that insulin signaling in the mediobasal hypothalamus (MBH) of rats is mandatory for lowering plasma BCAAs, most probably by inducing hepatic BCAA catabolism. Insulin receptor deletion only in agouti-related protein (AgRP)-expressing neurons (AgRP neurons) in the MBH impaired hepatic BCAA breakdown and suppression of plasma BCAAs during hyperinsulinemic clamps in mice. In support of this, chemogenetic stimulation of AgRP neurons in the absence of food significantly raised plasma BCAAs and impaired hepatic BCAA degradation. A prolonged fasting or ghrelin treatment recapitulated designer receptors exclusively activated by designer drugs-induced activation of AgRP neurons and increased plasma BCAAs. Acute stimulation of vagal motor neurons in the dorsal motor nucleus was sufficient to decrease plasma BCAAs. Notably, elevated plasma BCAAs were associated with impaired glucose homeostasis. These findings suggest a critical role of insulin signaling in AgRP neurons for BCAA regulation and raise the possibility that this control may be mediated primarily via vagal outflow. Furthermore, our results provide an opportunity to closely examine the potential mechanistic link between central nervous system-driven BCAA control and glucose homeostasis.
PMID: 33115827
ISSN: 1939-327x
CID: 4903142

Inflammation Meets Metabolism: Roles for the Receptor for Advanced Glycation End Products Axis in Cardiovascular Disease

Senatus, Laura; MacLean, Michael; Arivazhagan, Lakshmi; Egaña-Gorroño, Lander; López-Díez, Raquel; Manigrasso, Michaele B; Ruiz, Henry H; Vasquez, Carolina; Wilson, Robin; Shekhtman, Alexander; Gugger, Paul F; Ramasamy, Ravichandran; Schmidt, Ann Marie
Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.
PMID: 34178389
ISSN: 2084-6835
CID: 4936952

An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation

Arivazhagan, Lakshmi; Ruiz, Henry H; Wilson, Robin A; Manigrasso, Michaele B; Gugger, Paul F; Fisher, Edward A; Moore, Kathryn J; Ramasamy, Ravichandran; Schmidt, Ann Marie
The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.
PMID: 32437306
ISSN: 1524-4571
CID: 4446972

The Role of the Sympathetic Nervous System in Metabolic Disorder and Adipose Dysfunction in Obesity and Aging [Meeting Abstract]

Sakamoto, Kenichi; Zhou, Chunxue; Maurizi, Giulia; Liberini, Claudia; Li, Ling; Ruiz, Henry H; Buettner, Christoph
ISSN: 2472-1972
CID: 4903242

Advanced Glycation End Products: Building on the Concept of the "Common Soil" in Metabolic Disease

Ruiz, Henry H; Ramasamy, Ravichandran; Schmidt, Ann Marie
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.
PMID: 31638645
ISSN: 1945-7170
CID: 4168912

Myeloid Rage Protects From Insulin Resistance in Mice Fed High Fat Diet [Meeting Abstract]

Arivazhagan, Lakshmi; Ruiz, Henry; Wilson, Robin; Frye, Laura; Ramasamy, Ravichandran; Schmidt, Ann Marie
ISSN: 0009-7322
CID: 4903172