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419


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

Cardiometabolic disease: linking pathogenic mechanisms to therapeutic opportunities

Chavakis, Triantafyllos; Cosentino, Francesco; Schmidt, Ann Marie
PMID: 38244207
ISSN: 1755-3245
CID: 5633852

Continuous glucose monitoring captures glycemic variability in obesity after sleeve gastrectomy: A prospective cohort study

Dorcely, Brenda; DeBermont, Julie; Gujral, Akash; Reid, Migdalia; Vanegas, Sally M.; Popp, Collin J.; Verano, Michael; Jay, Melanie; Schmidt, Ann Marie; Bergman, Michael; Goldberg, Ira J.; Alemán, José O.
Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic β-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent β-cell dysfunction and the potential residual risk of diabetes complications.
SCOPUS:85181687648
ISSN: 2055-2238
CID: 5629132

Recipients of the 2024 Early Career Investigator Awards

Schmidt, Ann Marie
PMID: 38299359
ISSN: 1524-4636
CID: 5627262

Obesity research: Moving from bench to bedside to population

Schmidt, Ann Marie
Globally, obesity is on the rise. Research over the past 20 years has highlighted the far-reaching multisystem complications of obesity, but a better understanding of its complex pathogenesis is needed to identify safe and lasting solutions.
PMCID:10721162
PMID: 38048365
ISSN: 1545-7885
CID: 5612682

Involvement of the Receptor for Advanced Glycation End Products (RAGE) in high fat-high sugar diet-induced anhedonia in rats

Carr, Kenneth D; Weiner, Sydney P; Vasquez, Carolina; Schmidt, Ann Marie
Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.
PMCID:10592025
PMID: 37625475
ISSN: 1873-507x
CID: 5599112

Disruption of the productive encounter complex results in dysregulation of DIAPH1 activity

Theophall, Gregory G; Ramirez, Lisa M S; Premo, Aaron; Reverdatto, Sergey; Manigrasso, Michaele B; Yepuri, Gautham; Burz, David S; Ramasamy, Ravichandran; Schmidt, Ann Marie; Shekhtman, Alexander
The diaphanous-related formin, Diaphanous 1 (DIAPH1), is required for the assembly of Filamentous (F)-actin structures. DIAPH1 is an intracellular effector of the receptor for advanced glycation end products (RAGE) and contributes to RAGE signaling and effects such as increased cell migration upon RAGE stimulation. Mutations in DIAPH1, including those in the basic "RRKR" motif of its autoregulatory domain, diaphanous autoinhibitory domain (DAD), are implicated in hearing loss, macrothrombocytopenia, and cardiovascular diseases. The solution structure of the complex between the N-terminal inhibitory domain, DID, and the C-terminal DAD, resolved by NMR spectroscopy shows only transient interactions between DID and the basic motif of DAD, resembling those found in encounter complexes. Cross-linking studies placed the RRKR motif into the negatively charged cavity of DID. Neutralizing the cavity resulted in a 5-fold decrease in the binding affinity and 4-fold decrease in the association rate constant of DAD for DID, indicating that the RRKR interactions with DID form a productive encounter complex. A DIAPH1 mutant containing a neutralized RRKR binding cavity shows excessive colocalization with actin and is unresponsive to RAGE stimulation. This is the first demonstration of a specific alteration of the surfaces responsible for productive encounter complexation with implications for human pathology.
PMCID:10656230
PMID: 37832872
ISSN: 1083-351x
CID: 5604342

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Yepuri, Gautham; Ramirez, Lisa M; Theophall, Gregory G; Reverdatto, Sergei V; Quadri, Nosirudeen; Hasan, Syed Nurul; Bu, Lei; Thiagarajan, Devi; Wilson, Robin; Díez, Raquel López; Gugger, Paul F; Mangar, Kaamashri; Narula, Navneet; Katz, Stuart D; Zhou, Boyan; Li, Huilin; Stotland, Aleksandr B; Gottlieb, Roberta A; Schmidt, Ann Marie; Shekhtman, Alexander; Ramasamy, Ravichandran
Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
PMCID:10616211
PMID: 37903764
ISSN: 2041-1723
CID: 5610492

A randomized clinical trial comparing low-fat with precision nutrition-based diets for weight loss: impact on glycemic variability and HbA1c

Kharmats, Anna Y; Popp, Collin; Hu, Lu; Berube, Lauren; Curran, Margaret; Wang, Chan; Pompeii, Mary Lou; Li, Huilin; Bergman, Michael; St-Jules, David E; Segal, Eran; Schoenthaler, Antoinette; Williams, Natasha; Schmidt, Ann Marie; Barua, Souptik; Sevick, Mary Ann
BACKGROUND:Recent studies have demonstrated considerable interindividual variability in postprandial glucose response (PPGR) to the same foods, suggesting the need for more precise methods for predicting and controlling PPGR. In the Personal Nutrition Project, the investigators tested a precision nutrition algorithm for predicting an individual's PPGR. OBJECTIVE:This study aimed to compare changes in glycemic variability (GV) and HbA1c in 2 calorie-restricted weight loss diets in adults with prediabetes or moderately controlled type 2 diabetes (T2D), which were tertiary outcomes of the Personal Diet Study. METHODS:The Personal Diet Study was a randomized clinical trial to compare a 1-size-fits-all low-fat diet (hereafter, standardized) with a personalized diet (hereafter, personalized). Both groups received behavioral weight loss counseling and were instructed to self-monitor diets using a smartphone application. The personalized arm received personalized feedback through the application to reduce their PPGR. Continuous glucose monitoring (CGM) data were collected at baseline, 3 mo and 6 mo. Changes in mean amplitude of glycemic excursions (MAGEs) and HbA1c at 6 mo were assessed. We performed an intention-to-treat analysis using linear mixed regressions. RESULTS:We included 156 participants [66.5% women, 55.7% White, 24.1% Black, mean age 59.1 y (standard deviation (SD) = 10.7 y)] in these analyses (standardized = 75, personalized = 81). MAGE decreased by 0.83 mg/dL per month for standardized (95% CI: 0.21, 1.46 mg/dL; P = 0.009) and 0.79 mg/dL per month for personalized (95% CI: 0.19, 1.39 mg/dL; P = 0.010) diet, with no between-group differences (P = 0.92). Trends were similar for HbA1c values. CONCLUSIONS:Personalized diet did not result in an increased reduction in GV or HbA1c in patients with prediabetes and moderately controlled T2D, compared with a standardized diet. Additional subgroup analyses may help to identify patients who are more likely to benefit from this personalized intervention. This trial was registered at clinicaltrials.gov as NCT03336411.
PMID: 37236549
ISSN: 1938-3207
CID: 5508702

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