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Association between depression, happiness, and sleep duration: data from the UAE healthy future pilot study

Al Balushi, Mitha; Al Balushi, Sara; Javaid, Syed; Leinberger-Jabari, Andrea; Al-Maskari, Fatma; Al-Houqani, Mohammed; Al Dhaheri, Ayesha; Al Nuaimi, Abdullah; Al Junaibi, Abdullah; Oumeziane, Naima; Kazim, Marina; Al Hamiz, Aisha; Haji, Muna; Al Hosani, Ayesha; Abdel Wareth, Leila; AlMahmeed, Wael; Alsafar, Habiba; AlAnouti, Fatme; Al Zaabi, Eiman; K Inman, Claire; Shahawy, Omar El; Weitzman, Michael; Schmidt, Ann Marie; Sherman, Scott; Abdulle, Abdishakur; Ahmad, Amar; Ali, Raghib
BACKGROUND:The United Arab Emirates Healthy Future Study (UAEHFS) is one of the first large prospective cohort studies and one of the few studies in the region which examines causes and risk factors for chronic diseases among the nationals of the United Arab Emirates (UAE). The aim of this study is to investigate the eight-item Patient Health Questionnaire (PHQ-8) as a screening instrument for depression among the UAEHFS pilot participants. METHODS:The UAEHFS pilot data were analyzed to examine the relationship between the PHQ-8 and possible confounding factors, such as self-reported happiness, and self-reported sleep duration (hours) after adjusting for age, body mass index (BMI), and gender. RESULTS:Out of 517 participants who met the inclusion criteria, 487 (94.2%) participants filled out the questionnaire and were included in the statistical analysis using 100 multiple imputations. 231 (44.7%) were included in the primary statistical analysis after omitting the missing values. Participants' median age was 32.0 years (Interquartile Range: 24.0, 39.0). In total, 22 (9.5%) of the participant reported depression. Females have shown significantly higher odds of reporting depression than males with an odds ratio = 3.2 (95% CI:1.17, 8.88), and there were approximately 5-fold higher odds of reporting depression for unhappy than for happy individuals. For one interquartile-range increase in age and BMI, the odds ratio of reporting depression was 0.34 (95% CI: 0.1, 1.0) and 1.8 (95% CI: 0.97, 3.32) respectively. CONCLUSION/CONCLUSIONS:Females are more likely to report depression compared to males. Increasing age may decrease the risk of reporting depression. Unhappy individuals have approximately 5-fold higher odds of reporting depression compared to happy individuals. A higher BMI was associated with a higher risk of reporting depression. In a sensitivity analysis, individuals who reported less than 6 h of sleep per 24 h were more likely to report depression than those who reported 7 h of sleep.
PMCID:9587590
PMID: 36271400
ISSN: 2050-7283
CID: 5352582

"Blocking lipid uptake pathways does not prevent toxicity in adipose triglyceride lipase (ATGL) deficiency"

Oluwadare, Jide; Cabodevilla, Ainara G; Son, Ni-Huiping; Hu, Yunying; Mullick, Adam E; Verano, Michael; Alemán, Jose O; Ramasamy, Ravichandran; Goldberg, Ira J
Lipid accumulation in non-adipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human Neutral Lipid Storage Disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl knockout mice a low- or high-fat diet, we found heart lipid accumulation, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL-deficient mice through the generation of double knockout mice also deficient in either cardiac lipoprotein lipase (LpL) or cluster of differentiation (CD) 36, which is involved in an LpL-independent pathway for fatty acid uptake in the heart. We show neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo fatty acid synthesis. Thus, we conclude pathological storage of lipids in ATGL deficiency cannot be corrected by reducing heart lipid uptake.
PMID: 36115595
ISSN: 1539-7262
CID: 5336622

Effect of a Personalized Diet to Reduce Postprandial Glycemic Response vs a Low-fat Diet on Weight Loss in Adults With Abnormal Glucose Metabolism and Obesity: A Randomized Clinical Trial

Popp, Collin J; Hu, Lu; Kharmats, Anna Y; Curran, Margaret; Berube, Lauren; Wang, Chan; Pompeii, Mary Lou; Illiano, Paige; St-Jules, David E; Mottern, Meredith; Li, Huilin; Williams, Natasha; Schoenthaler, Antoinette; Segal, Eran; Godneva, Anastasia; Thomas, Diana; Bergman, Michael; Schmidt, Ann Marie; Sevick, Mary Ann
Importance:Interindividual variability in postprandial glycemic response (PPGR) to the same foods may explain why low glycemic index or load and low-carbohydrate diet interventions have mixed weight loss outcomes. A precision nutrition approach that estimates personalized PPGR to specific foods may be more efficacious for weight loss. Objective:To compare a standardized low-fat vs a personalized diet regarding percentage of weight loss in adults with abnormal glucose metabolism and obesity. Design, Setting, and Participants:The Personal Diet Study was a single-center, population-based, 6-month randomized clinical trial with measurements at baseline (0 months) and 3 and 6 months conducted from February 12, 2018, to October 28, 2021. A total of 269 adults aged 18 to 80 years with a body mass index (calculated as weight in kilograms divided by height in meters squared) ranging from 27 to 50 and a hemoglobin A1c level ranging from 5.7% to 8.0% were recruited. Individuals were excluded if receiving medications other than metformin or with evidence of kidney disease, assessed as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration equation, to avoid recruiting patients with advanced type 2 diabetes. Interventions:Participants were randomized to either a low-fat diet (<25% of energy intake; standardized group) or a personalized diet that estimates PPGR to foods using a machine learning algorithm (personalized group). Participants in both groups received a total of 14 behavioral counseling sessions and self-monitored dietary intake. In addition, the participants in the personalized group received color-coded meal scores on estimated PPGR delivered via a mobile app. Main Outcomes and Measures:The primary outcome was the percentage of weight loss from baseline to 6 months. Secondary outcomes included changes in body composition (fat mass, fat-free mass, and percentage of body weight), resting energy expenditure, and adaptive thermogenesis. Data were collected at baseline and 3 and 6 months. Analysis was based on intention to treat using linear mixed modeling. Results:Of a total of 204 adults randomized, 199 (102 in the personalized group vs 97 in the standardized group) contributed data (mean [SD] age, 58 [11] years; 133 women [66.8%]; mean [SD] body mass index, 33.9 [4.8]). Weight change at 6 months was -4.31% (95% CI, -5.37% to -3.24%) for the standardized group and -3.26% (95% CI, -4.25% to -2.26%) for the personalized group, which was not significantly different (difference between groups, 1.05% [95% CI, -0.40% to 2.50%]; P = .16). There were no between-group differences in body composition and adaptive thermogenesis; however, the change in resting energy expenditure was significantly greater in the standardized group from 0 to 6 months (difference between groups, 92.3 [95% CI, 0.9-183.8] kcal/d; P = .05). Conclusions and Relevance:A personalized diet targeting a reduction in PPGR did not result in greater weight loss compared with a low-fat diet at 6 months. Future studies should assess methods of increasing dietary self-monitoring adherence and intervention exposure. Trial Registration:ClinicalTrials.gov Identifier: NCT03336411.
PMID: 36169954
ISSN: 2574-3805
CID: 5334302

The receptor for advanced glycation end products and its ligands' expression in OVE26 diabetic sciatic nerve during the development of length-dependent neuropathy

Zglejc-Waszak, Kamila; Schmidt, Ann Marie; Juranek, Judyta K
Type 1 diabetes (T1D) may affect the peripheral nervous system and alter the expression of proteins contributing to inflammation and cellular cytoskeleton dysfunction, in most cases leading to the development of diabetic length-dependent neuropathy (DLDN). In the present study, we performed immunohistochemistry (IHC) to probe the expression of the receptor for advanced glycation end products (RAGE); its key ligands, high-mobility group box 1 (HMGB1), S100 calcium-binding protein B (S100B), and carboxymethyl-lysine (CML - advanced glycation end products (AGE)); and its cytoplasmic tail-binding partner, diaphanous related formin 1 (DIAPH1) and associated molecules, beta-actin (ACTB) and profilin 1 (PFN1) proteins in sciatic nerves harvested from seven-month old FVB/OVE26 mice with genetically-mediated T1D. We found that the amount of RAGE, HMGB1, and S100B proteins was elevated in diabetic vs the non-diabetic groups, while the amount of DIAPH1, ACTB, as well as PFN1 proteins did not differ between these groups. Moreover, our data revealed linear dependence between RAGE and HMGB1 proteins. Interaction criss-cross of selected sets of proteins in the sciatic nerve revealed that there were connected in a singular network. Our results indicate that T1D may alter expression patterns of RAGE axis proteins and thus contribute to DLDN.
PMID: 35915909
ISSN: 1440-1789
CID: 5287902

Aldose reductase promotes diet-induced obesity via induction of senescence in subcutaneous adipose tissue

Thiagarajan, Devi; Quadri, Nosirudeen; Jawahar, Shabnam; Zirpoli, Hylde; Del Pozo, Carmen Hurtado; López-Díez, Raquel; Hasan, Syed Nurul; Yepuri, Gautham; Gugger, Paul F; Finlin, Brian S; Kern, Philip A; Gabbay, Kenneth; Schmidt, Ann Marie; Ramasamy, Ravichandran
OBJECTIVE:Aldose reductase (AKR1B1 in humans; Akr1b3 in mice), a key enzyme of the polyol pathway, mediates lipid accumulation in the murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 in the pathogenesis of obesity and its complications. METHODS:The study employed mice treated with an inhibitor of aldose reductase or mice devoid of Akr1b3 were used to determine their response to a high-fat diet. The study used subcutaneous adipose tissue-derived adipocytes to investigate mechanisms by which AKR1B1/Akr1b3 promotes diet-induced obesity. RESULTS:Increased expression of aldose reductase and senescence in the adipose tissue of humans and mice with obesity were demonstrated. Genetic deletion of Akr1b3 or pharmacological blockade of AKRIB3 with zopolrestat reduced high-fat-diet-induced obesity, attenuated markers of adipose tissue senescence, and increased lipolysis. CONCLUSIONS:AKR1B1/Akr1b3 modulation of senescence in subcutaneous adipose tissue contributes to aberrant metabolic responses to high-fat feeding. These data unveil new opportunities to target these pathways to combat obesity.
PMID: 35894077
ISSN: 1930-739x
CID: 5276602

Soluble Receptor for Advanced Glycation End Products (sRAGE) Isoforms Predict Changes in Resting Energy Expenditure in Adults with Obesity during Weight Loss

Popp, Collin J; Zhou, Boyan; Manigrasso, Michaele B; Li, Huilin; Curran, Margaret; Hu, Lu; St-Jules, David E; Alemán, José O; Vanegas, Sally M; Jay, Melanie; Bergman, Michael; Segal, Eran; Sevick, Mary A; Schmidt, Ann M
Background/UNASSIGNED:Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives/UNASSIGNED:We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods/UNASSIGNED:Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results/UNASSIGNED:) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions/UNASSIGNED:This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.
PMCID:9071542
PMID: 35542387
ISSN: 2475-2991
CID: 5214412

The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie
Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand-receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.
PMCID:9102165
PMID: 35562970
ISSN: 1422-0067
CID: 5215052

Neuronal-glial communication perturbations in murine SOD1G93A spinal cord

MacLean, Michael; López-Díez, Raquel; Vasquez, Carolina; Gugger, Paul F; Schmidt, Ann Marie
Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by proteinaceous aggregate accumulation and neuroinflammation culminating in rapidly progressive lower and upper motor neuron death. To interrogate cell-intrinsic and inter-cell type perturbations in ALS, single-nucleus RNA sequencing was performed on the lumbar spinal cord in the murine ALS model SOD1G93A transgenic and littermate control mice at peri-symptomatic onset stage of disease, age 90 days. This work uncovered perturbed tripartite synapse functions, complement activation and metabolic stress in the affected spinal cord; processes evidenced by cell death and proteolytic stress-associated gene sets. Concomitantly, these pro-damage events in the spinal cord co-existed with dysregulated reparative mechanisms. This work provides a resource of cell-specific niches in the ALS spinal cord and asserts that interwoven dysfunctional neuronal-glial communications mediating neurodegeneration are underway prior to overt disease manifestation and are recapitulated, in part, in the human post-mortem ALS spinal cord.
PMID: 35228715
ISSN: 2399-3642
CID: 5174262

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) - Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Arivazhagan, Lakshmi; López-Díez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie
Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.
PMCID:9263181
PMID: 35811725
ISSN: 2297-055x
CID: 5279672

Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice

Manigrasso, Michaele B; Rabbani, Piul; Egaña-Gorroño, Lander; Quadri, Nosirudeen; Frye, Laura; Zhou, Boyan; Reverdatto, Sergey; Ramirez, Lisa S; Dansereau, Stephen; Pan, Jinhong; Li, Huilin; D'Agati, Vivette D; Ramasamy, Ravichandran; DeVita, Robert J; Shekhtman, Alexander; Schmidt, Ann Marie
[Figure: see text].
PMID: 34818060
ISSN: 1946-6242
CID: 5063702