Project description:Understanding the role of visceral fat accumulation in the occurrence and progression of metabolic syndrome is of considerable interest. In order to understand the difference between visceral tissue biology of healthy and unhealthy obese individuals, we have used microarray profiling to compare genome-wide expression differences between visceral adipose tissue biopsies obtained from obese diabetics, and those from age and body mass index (BMI) matched normal glucose tolerance subjects. Whereas genes upregulated in diabetics showed enrichment of natural killer cell mediated cytotoxicity, the downregulated genes showed enrichment of biosynthesis of unsaturated fatty acids. Given the known inhibitory effect of unsaturated fatty acids on inflammation and natural killer cell number or activity, our results suggest that visceral inflammation resulting from decreased levels of unsaturated fatty acids may underlie progression of diabetes in obese individuals.
Project description:Abstract Introduction: Asian Indians show “thin fat phenotype” characterized by higher visceral adipose tissue(VAT) and lower subcutaneous adipose tissue(SAT) mass and their higher cardio-metabolic risk has been attributed to this fat distribution. However, the underlying molecular pathology and role of these adipose depots in the pathogenesis of T2D in them remains unknown.Hypothesis: The comparison of transcription profiles of abdominal VAT and SAT and their correlation with diabetes related intermediate phenotypic traits could shed some light on their role in the pathophysiology of diabetes.MethodologySubjects: 19 diabetics (M: F ratio, 8:11) and 16 age and BMI matched controls (M: F ratio 5:11) undergoing abdominal surgery (non-malignant and non-infective conditions).Clinical Parameters: Anthropometry, Serum glucose, insulin, HOMA-R, HbA1c, lipid profile, FFA, adipocytokines. Abdominal VAT, SAT and liver fat were estimated by MRI.Adipose tissue biopsy: SAT and VAT samples were taken during surgery. Genome-wide gene expression profiling of these biopsies was performed using Affymetrix GeneChipPrimeView® arrays. The data was submitted to NCBI-GEO (Accession # GSE78721). Selected genes were validated by qPCR. Gene set enrichment analysis (GSEA) for functional and Weighted Gene Correlation Analysis (WGCNA) for statistical comparison was done.Results:Diabetics had higher waist circumference (p=0.05), HOMA-R (p=0.0002), Visceral fat content (p=0.02) and adipocyte size (p=0.02)GSEA: diabetics vs. controls: In VAT 16 gene sets were upregulated (FDR < 25%) enriching various immune system and inflammation-related pathways. In SAT too, various inflammatory genes were upregulated however they were statistically non-significant (FDR > 25%). Moreover, 12 out of 16 significantly enriched pathways in VAT were among the top 20 pathways in SAT. GSEA in diabetics: VAT vs SAT: None of the gene sets were found significant at FDR < 25% which substantiated our hypothesis that overall pathophysioloigcal alteration in both depots are similar. WGCNA for statistical comparison of VAT and SAT depots The correlation between measures of average gene expression and overall connectivity between both depots was significantly positive. Several modules of co-expressed genes in both VAT and SAT showed positive as well as negative correlation with various intermediate phenotypic traits of diabetes. In both depots they enriched several pathways otherwise known to be associated with pathological adipose tissue like inflammation, adipogenesis etc. Conclusions In Asian Indians, diabetes pathology inflicts similar molecular alternations in VAT and SAT, which are more intense in the former. The role of both adipose depots in the pathophysiology of diabetes is along similar lines and they enrich several molecular pathways which are otherwise known to be implicated in pathological adipose tissue.
Project description:We have identified molecular-level alternations in different adipose depots (thigh, visceral and subcutaneous) of Asian Indians (both male and female) suffering from type-2 diabetes as compared to age and BMI matched normal glucose tolerant subjects by functional analysis of differentially expressed genes, and correlation of gene expression estimates with measured intermediate traits associated with T2D and its related co-morbidities (Hb1Ac, HOMA-B, HOMA-R, NEFA, Triglyceride, Total Cholesterol, HDL, LDL, VLDL, Leptin, Adiponectin, TNF-α, Serum- Creatinine, IL-6, High sensitivity - serum-creatinine (hs-CRP) and also size of adipocytes). Funding: Grant Id: 5/4/8/2012-RMC Grant title: Clinical, Biochemical and Cellular Correlates of Transcriptome of Adipose Tissue Among Type-2 Diabetics Name of the funding source: Indian Council for Medical Research Overall design: We have recruited 30 controls & 30 diabetic subjects undergoing femur bone surgery and 16 controls & 19 diabetic subjects undergoing abdominal surgery (two samples from each subject, one subcutaneous and one visceral fat biopsy were extracted). So total 130 samples were obtained and analyzed for genome –wide gene expression profile of Adipocytes and infiltration macrophages from three different depots of adipose tissue.
Project description:Type 2 diabetes (T2D) is a complex disease with an elusive link between its molecular aetiology and clinical presentation. Although, the role of visceral adipose tissue in insulin-resistance and T2D is known, limited information is available on the role of peripheral-subcutaneous adipose tissue especially in Asian Indians. In this microarray-based study of diabetic and normal glucose tolerant Asian Indians, we generated the transcriptome of their thigh adipose tissue and analyzed differentially expressed genes (DEGs) using weighted gene co-expression network analysis; further we identified perturbed pathways implicated by these DEGs in relevant co-expression modules. We also attempted to link these pathways with known aspects of T2D pathophysiology in terms of their association with some of their intermediate traits, namely; adipocyte size, HOMA-B, HOMA-R, Hb1Ac, insulin, glucose-level, TNF-?, IL-6, VLDLs, LDLs, HDLs, and NEFAs. It was observed that several modules of co-expressed genes show an association with diabetes and some of its intermediate phenotypic traits mentioned above. Therefore, these findings suggest a role of peripheral subcutaneous adipose tissue in the pathophsiology of T2D in Asian Indians. Additionally, our study indicated that the peripheral subcutaneous adipose tissue in diabetics shows pathologic changes characterized by adipocyte hypertrophy and up-regulation of inflammation-related pathways.
Project description:The roles of abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) in the molecular pathogenesis type-2 diabetics (T2D) among Asian Indians showing a "thin fat" phenotype largely remains obscure. In this study, we generated transcription profiles in biopsies of these adipose depots obtained during surgery in 19 diabetics (M: F ratio, 8:11) and 16 (M: F ratio 5:11) age- and BMI-matched non-diabetics. Gene set enrichment analysis (GSEA) was used for comparing transcription profile and showed that 19 gene sets, enriching inflammation and immune system-related pathways, were upregulated in diabetics with F.D.R. <25% and >25%, respectively, in VAT and SAT. Moreover, 13 out of the 19 significantly enriched pathways in VAT were among the top 20 pathways in SAT. On comparison of VAT vs. SAT among diabetics, none of the gene sets were found significant at F.D.R. <25%. The Weighted Gene Correlation Analysis (WGCNA) analysis of the correlation between measures of average gene expression and overall connectivity between VAT and SAT was significantly positive. Several modules of co-expressed genes in both the depots showed a bidirectional correlation with various diabetes-related intermediate phenotypic traits. They enriched several diabetes pathogenicity marker pathways, such as inflammation, adipogenesis, etc. It is concluded that, in Asian Indians, diabetes pathology inflicts similar molecular alternations in VAT and SAT, which are more intense in the former. Both adipose depots possibly play a role in the pathophysiology of T2D, and whether it is protective or pathogenic also depends on the nature of modules of co-expressed genes contained in them.
Project description:T2D is a complex disease with poorly understood mechanisms. In Asian Indians, it is associated with "thin fat" phenotype which resembles with partial lipodystrophy. We hypothesized that disturbed expression of lipodystrophy genes might play a role in T2D pathogenesis. Therefore, we attempted to establish a link between these two diseases by studying the overlap between the network of lipodystrophy genes and the differentially expressed genes (DEGs) in the peripheral subcutaneous adipose tissue of Asian Indians diabetics. We found that 16, out of 138 lipodystrophy genes were differentially regulated in diabetics and around 18% overlap between their network and the DEGs; the expression level of lipodystrophy genes showed an association with disease-related intermediate phenotypic traits among diabetics but not in the control group. We also attempted to individualize the diabetic patients based on ±2 fold altered expression of lipodystrophy genes as compared to their average expression in the control group. In conclusion, significant overlap exists between some of the lipodystrophy genes and their network with DEGs in the peripheral adipose tissue in diabetics. They possibly play a role in the pathogenesis of diabetes and individualization of diabetics is possible based on their altered expression in their peripheral adipose tissue.
Project description:Background:Visceral adipose tissue (VAT) assessment is limited in clinical practice due to expensive, time consuming and limited availability of MRI and DXA machines. We explored the utility of a recently developed Metabolic Score for Visceral Fat (METS-VF) to assess VAT in south Asian individuals with morbid obesity. Patients and Methods:Individuals with BMI ?35 kg/m2 aged between 30 and 60 years were randomly selected from a database of individuals with morbid obesity, attending a multi-disciplinary bariatric clinic in a tertiary care teaching hospital in southern India. Body composition was assessed by using a Hologic Discovery A dual-energy X-ray absorptiometry (DXA) machine. METS-VF was used to estimate VAT by using a previously published algorithm. Results:The mean age and body mass index of the study subjects (N=350) were 38.2 years and 40.1 kg/m2. The MET-VF score performed satisfactorily (AUC of 0.78 (95% CI 0.72-0.85)) for predicting an increased visceral adipose tissue (VAT area ? 163 cm2) as detected by DXA. A METS-VF value of 7.3 was found to have a good sensitivity and reasonable specificity in predicting elevated VAT in this population. Conclusion:This is the first study to validate the utility of METS-VF as a surrogate measure of visceral adiposity in south Indian individuals with morbid obesity. Given the simplicity, easy availability, reliability and inexpensive nature of this obesity indicator, it may find its widespread use in lower middle-income countries.
Project description:<h4>Objective</h4>The aim of this study was to investigate the independent associations between age-specific annual weight gain from birth to age 4 years and fat deposition in metabolically distinct compartments at age 4.5 years in a South Asian longitudinal birth cohort.<h4>Methods</h4>Volumetric abdominal magnetic resonance imaging with comprehensive segmentation of deep and superficial subcutaneous adipose tissue (SAT) and visceral adipose tissues (VAT) was performed in 316 children (150 boys and 166 girls in three ethnic groups; 158 Chinese, 94 Malay, and 64 Indian) aged 4.5 years. Associations between fat volumes and annual relative weight gain conditional on past growth were assessed overall and stratified by sex and ethnicity.<h4>Results</h4>Conditional relative weight gain had stronger associations with greater SAT and VAT at age 4.5 years in girls than boys and in Indians compared with Malay and Chinese. Overall, the magnitude of association was the largest during 2 to 3 years for SAT and 1 to 2 years for VAT. Despite similar body weight, Indian children and girls had the highest deep and superficial SAT volumes at age 4.5 years (all interactions P < 0.05). No significant sex or ethnic differences were observed in VAT. With increasing BMI, Indian children had the highest tendency to accumulate VAT, and girls accumulated more fat than boys in all depots (all interactions P < 0.001).<h4>Conclusions</h4>Indian ethnicity and female sex predisposed children to accumulate more fat in the VAT depot with increasing conditional relative weight gain in the second year of life. Thus, 1 to 2 years of age may be a critical window for interventions to reduce visceral fat accumulation.
Project description:OBJECTIVES: Visceral adipose tissue (VAT) is an independent risk factor in cardiometabolic diseases and is commonly measured by computed tomography (CT). It is measured clinically by waist circumference (WC). The L4/5 intervertebral space VAT (L4/5 VAT) is traditionally used to represent total VAT volume. We set out to determine (1) the level of intervertebral space on CT that best approximates the total VAT volume; (2) compare the association between WC and VAT in Singaporean Chinese and Indian; and (3) examine the correlation between VAT and cardiometabolic risk factors. SUBJECTS: A total of 60 Chinese and 60 Asian Indian men older than 60 years were recruited. Their medical history was taken and anthropometry was measured. Fasting glucose, insulin, lipids, adipokines and inflammatory markers were measured. Insulin resistance was evaluated by homeostasis model assessment-insulin resistance. VAT was determined by CT. Total VAT volume was calculated in 22 patients from VAT areas at seven intervertebral levels. The optimal VAT area most representative of total VAT volume was determined and used for all patients to approximate total VAT volume. RESULTS: The VAT area at L2/3 intervertebral space (L2/3 VAT) correlated almost perfectly with VAT volume (R(2)=0.974 and 0.946 for Chinese and Indians, respectively). SUBJECTS from the two races had similar height, weight, body mass index (BMI), WC and L2/3 VAT but more Indian men had hypertension, hyperlipidemia and type 2 diabetes mellitus. WC was correlated with the L2/3 VAT area in both Chinese (r=0.484, P<0.001) and Indian subjects (r=0.366, P=0.004) without racial difference (P=0.2 for interaction term). L2/3 VAT also correlated better with cardiometabolic risk factors, adipokines and C-reactive protein than WC, BMI or L4/5 VAT. CONCLUSION: The L2-L3 intervertebral space was the best anatomic level for a single-slice CT cross-sectional area measurement of VAT to approximate total body visceral adipose volume in this population of Chinese and Asian Indian men older than 60 years. L2/3 VAT was better correlated with multiple cardiovascular risk factors, adipokines and inflammatory marker than either L4/5 VAT, WC or BMI.
Project description:BACKGROUND:South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS:In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS:In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (-?3.9?±?3.6 kg vs -?0.6?±?2.2 kg; mean change from baseline (liraglutide vs placebo): -?3.5 kg; 95% CI [-?5.3, -?1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (-?23?±?27 cm2 vs -?2?±?17 cm2; mean change from baseline (liraglutide vs placebo): -?17 cm2; 95% CI [-?32, -?3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (-?1.0?±?0.8% (-?10.5?±?9.1 mmol/mol)) vs (-?0.6?±?0.8% (-?6.1?±?8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): -?0.6% (-?6.5 mmol/mol); 95% CI [-?1.1, -?0.1 (-?11.5, -?1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (?: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS:While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.