Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 24
Filter
1.
J Med Educ Curric Dev ; 10: 23821205231207213, 2023.
Article in English | MEDLINE | ID: mdl-38033379

ABSTRACT

OBJECTIVES: Determining the level of satisfaction in each field will help to examine and eliminate the existing problems and shortcomings. Using this information, students' satisfaction can be provided as much as possible while strengthening the positive factors and correcting the negative factors. The aim of this study was to evaluate the Student's Satisfaction with externship Education in the Academic Departments of the Medical School of Kermanshah University of Medical Sciences in 2021. METHODS: This descriptive cross-sectional study, was performed in the medical school of Kermanshah University of Medical Sciences. The statistical population was all externship students. The validity of the questionnaire's content was determined by consulting experts, and its reliability was obtained by Cronbach's alpha method based on a sample of 20 students. The questionnaires were completed virtually on the Google site using the Google Form. Data analysis was performed Stata V14.2 software using descriptive statistics, t-test, and chi-square, and the significant level was considered 0.05. RESULTS: The results showed that 55% of the participants were female and 45% were male. The level of students 'satisfaction with the quality of supervisors' education was moderate to high and in other cases was moderate to low. Students were more satisfied with teaching anesthesia than other departments and were dissatisfied with the infectious department. No statistically significant difference was found between people's satisfaction with the overall clinical education process in terms of age. CONCLUSION: The results of this study showed that students have moderate to poor satisfaction with externship education in educational groups.

3.
Cell Genom ; 2(1)2022 Jan 12.
Article in English | MEDLINE | ID: mdl-35530816

ABSTRACT

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10-9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.

4.
Nat Commun ; 12(1): 3626, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34131117

ABSTRACT

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.


Subject(s)
Blood Platelets/metabolism , Chromosome Mapping , Whole Genome Sequencing , Base Sequence , GTP-Binding Proteins , Genome-Wide Association Study , HEK293 Cells , Humans , K562 Cells , Phenotype , Platelet Aggregation , Platelet Function Tests , Polymorphism, Single Nucleotide , Quantitative Trait Loci , RGS Proteins/genetics , RGS Proteins/metabolism , Receptors, Cell Surface/genetics , Thrombosis/genetics
5.
Nat Commun ; 11(1): 1122, 2020 02 28.
Article in English | MEDLINE | ID: mdl-32111823

ABSTRACT

Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure.


Subject(s)
Actinin/genetics , Genetic Predisposition to Disease/genetics , Heart Failure/genetics , ABO Blood-Group System/genetics , Atrial Fibrillation/genetics , Chromosomes, Human, Pair 1 , Enhancer Elements, Genetic , Gene Expression Regulation , Genome-Wide Association Study , Heart Failure/pathology , Human Embryonic Stem Cells/cytology , Humans , Musculoskeletal Diseases/genetics , Myocytes, Cardiac/cytology , Polymorphism, Single Nucleotide , Quantitative Trait Loci
6.
J Cardiovasc Electrophysiol ; 30(11): 2627-2628, 2019 11.
Article in English | MEDLINE | ID: mdl-31502372

ABSTRACT

Pulmonary vein isolation (PVI) is the only proven ablation strategy for paroxysmal and persistent atrial fibrillation (AF). However, when AF recurs despite durable PVI in a subgroup of patients with persistent AF, there is no scientifically proven ablation strategy to pursue. Here, we summarized how we approach persistent AF at Johns Hopkins Hospital.


Subject(s)
Atrial Fibrillation/physiopathology , Atrial Fibrillation/surgery , Catheter Ablation/methods , Aged , Atrial Fibrillation/diagnosis , Female , Humans , Pulmonary Veins/surgery , Time Factors , Treatment Outcome
8.
Platelets ; 30(3): 380-386, 2019.
Article in English | MEDLINE | ID: mdl-29553866

ABSTRACT

Coronary artery disease (CAD) remains a major cause of mortality and morbidity worldwide. The aggregation of activated platelets on a ruptured atherosclerotic plaque is a critical step in most acute cardiovascular events like myocardial infarction. Platelet aggregation both at baseline and after aspirin is highly heritable. Genome-wide association studies (GWAS) have identified a common variant within the first intron of the platelet endothelial aggregation receptor1 (PEAR1), to be robustly associated with platelet aggregation. In this study, we used targeted deep sequencing to fine-map the prior GWAS peak and identify additional rare variants of PEAR1 that account for missing heritability in platelet aggregation within the GeneSTAR families. In this study, 1709 subjects (1043 European Americans, EA and 666 African Americans, AA) from families in the GeneSTAR study were included. In vitro platelet aggregation in response to collagen, ADP and epinephrine was measured at baseline and 14 days after aspirin therapy (81 mg/day). Targeted deep sequencing of PEAR1 in addition to 2kb of upstream and downstream of the gene was performed. Under an additive genetic model, the association of single variants of PEAR1 with platelet aggregation phenotypes were examined. Additionally, we examined the association between the burden of PEAR1 rare non-synonymous variants and platelet aggregation phenotypes. Of 532 variants identified through sequencing, the intron 1 variant, rs12041331, was significantly associated with all platelet aggregation phenotypes at baseline and after platelet inhibition with aspirin therapy. rs12566888, which is in linkage disequilibrium with rs12041331, was associated with platelet aggregation phenotypes but to a lesser extent. In the EA families, the burden of PEAR1 missense variants was associated with platelet aggregation after aspirin therapy when the platelets were stimulated with epinephrine (p = 0.0009) and collagen (p = 0.03). In AAs, the burden of PEAR1 missense variants was associated, to a lesser degree, with platelet aggregation in response to epinephrine (p = 0.02) and ADP (p = 0.04). Our study confirmed that the GWAS-identified variant, rs12041331, is the strongest variant associated with platelet aggregation both at baseline and after aspirin therapy in our GeneSTAR families in both races. We identified additional association of rare missense variants in PEAR1 with platelet aggregation following aspirin therapy. However, we observed a racial difference in the contribution of these rare variants to the platelet aggregation, most likely due to higher residual missing heritability of platelet aggregation after accounting for rs12041331 in the EAs compared to AAs.


Subject(s)
Platelet Aggregation/immunology , Platelet Function Tests/methods , Receptors, Cell Surface/immunology , Black or African American , Female , Humans , Male , Middle Aged , White People
9.
Circ Cardiovasc Imaging ; 11(9): e007546, 2018 09.
Article in English | MEDLINE | ID: mdl-30354675

ABSTRACT

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy characterized by fibrofatty replacement of right ventricular myocardium resulting in reentrant ventricular tachycardia (VT). Cardiac magnetic resonance imaging (CMR) can noninvasively measure regional abnormalities using tissue-tracking strain as well as late gadolinium enhancement (LGE). In this study, we examine arrhythmogenic substrate using regional CMR strain, LGE, and electroanatomic mapping (EAM) in arrhythmogenic right ventricular cardiomyopathy patients presenting for VT ablation. METHODS AND RESULTS: Twenty-one patients underwent right ventricular endocardial EAM, whereas 17 underwent epicardial EAM, to detect dense scar (<0.5 mV) as well as CMR study within 12 months. Quantitative regional strain analysis was performed in all 21 patients, although the presence of LGE was visually examined in 17 patients. Strain was lower in segments with dense scar on endocardial and epicardial EAM (-9.7±4.1 versus -7.3±4.0, and -9.8±2.8 versus -7.6±3.8; P<0.05), in segments with LGE scar (-9.9±4.4 versus -6.0±3.6; P=0.001), and at VT culprit sites (-7.4±3.7 versus -10.1±4.1; P<0.001), compared with the rest of right ventricular. On patient-clustered analysis, a unit increase in strain was associated with 21% and 18% decreased odds of scar on endocardial and epicardial EAM, respectively, 17% decreased odds of colocalizing VT culprit site, and 43% decreased odds of scar on LGE-CMR ( P<0.05 for all). LGE and EAM demonstrated poor agreement with κ=0.18 (endocardial, n=17) and κ=0.06 (epicardial, n=13). Only 8 (15%) VT termination sites exhibited LGE. CONCLUSIONS: Regional myocardial strain on cine CMR improves detection of arrhythmogenic VT substrate compared with LGE. This may enhance diagnostic accuracy of CMR in arrhythmogenic right ventricular cardiomyopathy without the need for invasive procedures and facilitate the planning of VT ablation procedures.


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/diagnostic imaging , Contrast Media/administration & dosage , Gadolinium DTPA/administration & dosage , Heart Ventricles/diagnostic imaging , Magnetic Resonance Imaging, Cine , Myocardial Contraction , Myocardium/pathology , Ventricular Function, Right , Adult , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmogenic Right Ventricular Dysplasia/pathology , Arrhythmogenic Right Ventricular Dysplasia/physiopathology , Catheter Ablation , Electrophysiologic Techniques, Cardiac , Female , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Heart Ventricles/surgery , Humans , Male , Predictive Value of Tests , Retrospective Studies , Risk Factors , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/surgery , Treatment Outcome , Young Adult
10.
J Electrocardiol ; 51(5): 801-808, 2018.
Article in English | MEDLINE | ID: mdl-30177316

ABSTRACT

BACKGROUND: View into Ventricular Onset (VIVO) is a novel ECGI system that uses 3D body surface imaging, myocardial CT/MRI, and 12­lead ECG to localize earliest ventricular activation through analysis of simulated and clinical vector cardiograms. OBJECTIVE: To evaluate the accuracy of VIVO for the localization of ventricular arrhythmias (VA). METHODS: In twenty patients presenting for catheter ablation of VT [8] or PVC [12], VIVO was used to predict the site earliest activation using 12­lead ECG of the VA. Results were compared to invasive electroanatomic mapping (EAM). RESULTS: A total of 22 PVC/VT morphologies were analyzed using VIVO. VIVO accurately predicted the location of the VA in 11/13 PVC cases and 8/9 VT cases. VIVO correctly predicted right vs left ventricular foci in 20/22 cases. CONCLUSION: View into Ventricular Onset (VIVO) can accurately predict earliest activation of VA, which could aid in catheter ablation, and should be studied further.


Subject(s)
Electrocardiography/methods , Tachycardia, Ventricular/diagnosis , Ventricular Premature Complexes/diagnosis , Adult , Aged , Body Surface Potential Mapping/methods , Catheter Ablation , Female , Heart/anatomy & histology , Heart/diagnostic imaging , Humans , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Middle Aged , Myocardium/pathology , Patient-Specific Modeling , Pilot Projects , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/surgery , Tomography, X-Ray Computed , Ventricular Premature Complexes/physiopathology , Ventricular Premature Complexes/surgery
11.
JACC Clin Electrophysiol ; 4(1): 59-68, 2018 01.
Article in English | MEDLINE | ID: mdl-29520376

ABSTRACT

Background: Bipolar voltage mapping, as part of atrial fibrillation (AF) ablation, is traditionally performed in a point-by-point (PBP) approach using single-tip ablation catheters. Alternative techniques for fibrosis-delineation include fast-anatomical mapping (FAM) with multi-electrode circular catheters, and late gadolinium-enhanced magnetic-resonance imaging (LGE-MRI). The correlation between PBP, FAM, and LGE-MRI fibrosis assessment is unknown. Objective: In this study, we examined AF substrate using different modalities (PBP, FAM, and LGE-MRI mapping) in patients presenting for an AF ablation. Methods: LGE-MRI was performed pre-ablation in 26 patients (73% males, age 63±8years). Local image-intensity ratio (IIR) was used to normalize myocardial intensities. PBP- and FAM-voltage maps were acquired, in sinus rhythm, prior to ablation and co-registered to LGE-MRI. Results: Mean bipolar voltage for all 19,087 FAM voltage points was 0.88±1.27mV and average IIR was 1.08±0.18. In an adjusted mixed-effects model, each unit increase in local IIR was associated with 57% decrease in bipolar voltage (p<0.0001). IIR of >0.74 corresponded to bipolar voltage <0.5 mV. A total of 1554 PBP-mapping points were matched to the nearest FAM-point. In an adjusted mixed-effects model, log-FAM bipolar voltage was significantly associated with log-PBP bipolar voltage (ß=0.36, p<0.0001). At low-voltages, FAM-mapping distribution was shifted to the left compared to PBP-mapping; at intermediate voltages, FAM and PBP voltages were overlapping; and at high voltages, FAM exceeded PBP-voltages. Conclusion: LGE-MRI, FAM and PBP-mapping show good correlation in delineating electro-anatomical AF substrate. Each approach has fundamental technical characteristics, the awareness of which allows proper assessment of atrial fibrosis.


Subject(s)
Atrial Fibrillation , Electrophysiologic Techniques, Cardiac , Heart Atria , Image Interpretation, Computer-Assisted , Magnetic Resonance Imaging , Aged , Atrial Fibrillation/diagnostic imaging , Atrial Fibrillation/physiopathology , Atrial Fibrillation/surgery , Catheter Ablation , Female , Heart Atria/diagnostic imaging , Heart Atria/physiopathology , Humans , Male , Middle Aged , Models, Cardiovascular , Prospective Studies
12.
Pacing Clin Electrophysiol ; 41(4): 345-352, 2018 04.
Article in English | MEDLINE | ID: mdl-29405366

ABSTRACT

AIMS: Prior studies identified a relationship between epicardial bipolar and endocardial unipolar voltage. Whether the relationship is valid with smaller multielectrode mapping catheters has not been reported. We explored the association of right ventricular (RV) endocardial unipolar voltage mapping with epicardial bipolar voltage mapping using a multielectrode mapping catheter. METHODS: Electrograms from patients who underwent multielectrode endocardial and epicardial RV electroanatomical mapping during ablation procedures were analyzed. Each endocardial mapping point was matched to the corresponding nearest epicardial point. The correlation between unipolar endocardial voltage and epicardial bipolar voltage was determined. The optimal unipolar threshold to detect epicardial low voltage (< 1.0 mV) and dense scar (0.5 mV) was calculated. RESULTS: A total of 4,895 points were analyzed. There was a significant correlation between endocardial unipolar and epicardial bipolar voltage (Spearman rho  =  0.499, P  =  < 0.001). The extent of the correlation was inversely associated with wall thickness. The receiver operator characteristic analysis of endocardial unipolar voltage predicting epicardial bipolar voltage of < 1.0 mV and < 0.5 showed an area under the curve of 0.769 and 0.812, respectively. The endocardial unipolar voltage that had the highest sensitivity and specificity in detecting epicardial bipolar voltage of < 1.0 mV and < 0.5 mV was 3.3 mV (70.3% sensitivity, 70.3% specificity), and 2.8 mV (sensitivity 73.8%, specificity 73.3%), respectively. CONCLUSION: Epicardial low voltage of the RV can be assessed by unipolar endocardial voltage using small multielectrode catheters. The strength of the association was inversely correlated with the wall thickness.


Subject(s)
Catheter Ablation , Cicatrix/physiopathology , Epicardial Mapping/methods , Heart Ventricles/physiopathology , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/surgery , Adult , Epicardial Mapping/instrumentation , Female , Heart Conduction System/physiopathology , Humans , Male , Retrospective Studies
13.
Circulation ; 137(3): 307-309, 2018 01 16.
Article in English | MEDLINE | ID: mdl-29046319
14.
J Cardiovasc Electrophysiol ; 28(10): 1189-1195, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28727191

ABSTRACT

INTRODUCTION: Epicardial ablation is becoming an important part of management in patients with ventricular tachycardia (VT). Posterior epicardial access via the Sosa or needle-in-needle (NIN) approach for epicardial VT ablation is considered to be the method of choice for most electrophysiologists. Anterior epicardial access as an alternative technique has recently been proposed, but there are limited data about its safety, efficacy, and the rate of immediate complications. In this study, we report our experience with anterior epicardial access between 2009 and 2016. METHODS: Between 2009 and June 2016, 100 consecutive patients underwent epicardial VT ablation using an anterior approach. The success rate, epicardial bleeding, and other complications related to the epicardial access in these patients were compared to the previously reported rate of complications in patients whom epicardial access was performed using the NIN or Sosa techniques. RESULTS: Anterior epicardial access was obtained successfully in 100% of patients in the first attempt. The success rate of the anterior approach was comparable with the reported success rate of the NIN technique (100% vs. 100%, P value not significant) but better than the Sosa technique (100% vs. 94%, P = 0.012). None of the patients in the anterior approach series suffered from significant pericardial bleeding (defined as greater than 80 mL of blood loss), RV puncture/damage, or need for an emergent cardiac surgery. CONCLUSION: An anterior epicardial approach is feasible and appears to have an acceptable safety profile in comparison with other epicardial approaches.


Subject(s)
Catheter Ablation/methods , Pericardium/physiopathology , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/therapy , Catheter Ablation/adverse effects , Electrophysiological Phenomena , Epicardial Mapping , Hemorrhage/epidemiology , Hemorrhage/etiology , Hospitalization , Humans , Magnetic Resonance Imaging , Pericardium/diagnostic imaging , Postoperative Complications/epidemiology , Tachycardia, Ventricular/diagnostic imaging , Tertiary Care Centers , Tomography, X-Ray Computed , Treatment Outcome
15.
Clin Med Insights Cardiol ; 11: 1179546817709787, 2017.
Article in English | MEDLINE | ID: mdl-28607545

ABSTRACT

Aortopathies pose a significant healthcare burden due to excess early mortality, increasing incidence, and underdiagnosis. Understanding the underlying genetic causes, early diagnosis, timely surveillance, prophylactic repair, and family screening are keys to addressing these diseases. Next-generation sequencing continues to expand our understanding of the genetic causes of heritable aortopathies, rapidly clarifying their underlying molecular pathophysiology and suggesting new potential therapeutic targets. This review will summarize the pathogenetic mechanisms and management of heritable genetic aortopathies with attention to specific forms of both syndromic and nonsyndromic disorders, including Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial thoracic aortic aneurysm and dissection.

17.
Cardiol Res ; 7(3): 119-121, 2016 Jun.
Article in English | MEDLINE | ID: mdl-28197279

ABSTRACT

We report the case of a 79-year-old woman who presented to our hospital for elective removal of an infratentorial meningioma and suffered a periprocedural cardiac arrest. Shortly after uncomplicated induction of anesthesia prior to the surgery, the patient became hypotensive and bradycardic, culminating ultimately in a cardiac arrest with pulseless electrical activity. Return of spontaneous circulation occurred within 90 seconds of arrest, but the patient remained dependent on maximal doses of epinephrine and dopamine for hemodynamic support. Echocardiography performed on the day of cardiac arrest revealed a newly depressed left ventricular ejection fraction (LVEF) of 15-20% with an apical ballooning pattern. Left heart catheterization showed no obstructive coronary lesions to explain her depressed ejection fraction. A diagnosis of stress cardiomyopathy (SCM) was made given the echocardiographic findings and absence of concomitant coronary disease. Within the next 24 hours, the patient was liberated from inotropic support, and at 6-month follow-up, her LVEF returned to 55% and she had no heart failure symptoms.

19.
N Engl J Med ; 370(20): 1909-1919, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24827035

ABSTRACT

BACKGROUND: Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. METHODS: We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. RESULTS: A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. CONCLUSIONS: These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.).


Subject(s)
Genetic Predisposition to Disease , Metabolic Syndrome/genetics , Mutation , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Coronary Artery Disease/genetics , Diabetes Mellitus, Type 2/genetics , Exome , Female , Founder Effect , Genetic Linkage , Glucose-6-Phosphatase/metabolism , Humans , Hypertension/genetics , Male , Obesity, Abdominal/genetics , Pedigree , Dyrk Kinases
20.
J Biol Chem ; 287(10): 7213-23, 2012 Mar 02.
Article in English | MEDLINE | ID: mdl-22232553

ABSTRACT

Body fat, insulin resistance, and type 2 diabetes are often linked together, but the molecular mechanisms that unify their association are poorly understood. Wnt signaling regulates adipogenesis, and its altered activity has been implicated in the pathogenesis of type 2 diabetes and metabolic syndrome. LRP6(+/-) mice on a high fat diet were protected against diet-induced obesity and hepatic and adipose tissue insulin resistance compared with their wild-type (WT) littermates. Brown adipose tissue insulin sensitivity and reduced adiposity of LRP6(+/-) mice were accounted for by diminished Wnt-dependent mTORC1 activity and enhanced expression of brown adipose tissue PGC1-α and UCP1. LRP6(+/-) mice also exhibited reduced endogenous hepatic glucose output, which was due to diminished FoxO1-dependent expression of the key gluconeogenic enzyme glucose-6-phosphatase (G6pase). In addition, in vivo and in vitro studies showed that loss of LRP6 allele is associated with increased leptin receptor expression, which is a likely cause of hepatic insulin sensitivity in LRP6(+/-) mice. Our study identifies LRP6 as a nutrient-sensitive regulator of body weight and glucose metabolism and as a potential target for pharmacological interventions in obesity and diabetes.


Subject(s)
Adipose Tissue, Brown/metabolism , Energy Metabolism/physiology , Glucose/metabolism , Homeostasis/physiology , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Mitochondria/metabolism , Adiposity/physiology , Alleles , Animals , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Dietary Fats/adverse effects , Dietary Fats/pharmacology , Energy Metabolism/drug effects , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gluconeogenesis/physiology , Glucose/genetics , Glucose-6-Phosphatase/genetics , Glucose-6-Phosphatase/metabolism , Homeostasis/drug effects , Insulin Resistance/genetics , Low Density Lipoprotein Receptor-Related Protein-6/genetics , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Knockout , Mitochondria/genetics , Multiprotein Complexes , Obesity/chemically induced , Obesity/genetics , Obesity/metabolism , Proteins/genetics , Proteins/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolism , TOR Serine-Threonine Kinases , Wnt Signaling Pathway/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...