Transcriptome profiling reveals association of peripheral adipose tissue pathology with type-2 diabetes in Asian Indians

Saxena, Aditya; Tiwari, Prabhat; Wahi, Nitin; Soni, Arpana; Bansiwal, Ram Chandra; Kumar, Anshul; Sharma, Balram; Punjabi, Prakash P; Gupta, Nidhi; Malik, Babita; Medicherla, Krishna Mohan; Suravajhala, Prashanth; Mathur, Sandeep Kumar

doi:10.1080/21623945.2019.1595269

Cited by 23 publications

(26 citation statements)

References 33 publications

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“…Keeping in view the fact that diabetics had larger adipocyte size (although statistically insignificant in subcutaneous adipose depot), the modules of co-expressed genes in both depots showed association with its intermediate phenotypic traits and these modules of co-expressed genes enriched inflammation- and adipogenesis-related pathways; all such findings suggest that diabetes is associated with pathologic adipose tissue in both compartments. In two recent studies [ 38 , 62 ], we showed that diabetes is associated with similar pathologic changes in peripheral subcutaneous adipose tissue, and these pathologic changes show an association with diabetes-related intermediate phenotypic traits. Taken together, this evidence explains that the “thin fat” phenotype of Asian Indians is due to qualitative pathologic alterations in the adipose tissue.…”

Section: Discussionmentioning

confidence: 76%

“…As far as the Asian Indians are concerned, few studies point towards a potential role of subcutaneous abdominal adipose tissue in the pathogenesis of insulin resistance and possibly diabetes [ 37 ], but more studies are lacking. Recently we revealed the association between transcription profiles of peripheral subcutaneous adipose tissue and diabetes-related intermediate phenotypic traits of diabetes [ 38 ]. Whether this fat depot plays a causative or protective role in the pathogenesis of diabetes was not clarified by the study.…”

Section: Introductionmentioning

confidence: 99%

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The Transcriptomic Evidence on the Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indians Indicates the Involvement of Both

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

The Transcriptomic Evidence on the Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indians Indicates the Involvement of Both

et al. 2020

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“…In the present study, these transcription profiling datasets were furtherer processed using Bioconductor package gcrma [10]. A non-specific filtering step was then carried out to select high sensitivity probes using package genefilter [8]. Differential gene expression was estimated using limma [9].…”

Section: Methodsmentioning

confidence: 99%

“…Table 1 presents gender-wise measured anthropometric, and biochemical parameters. The clinical information with detailed methodology has been published elsewhere [ 8 , 9 ].…”

Section: Methodsmentioning

confidence: 99%

The common pathophysiologic threads between Asian Indian diabetic’s ‘Thin Fat Phenotype’ and partial lipodystrophy: the peripheral adipose tissue transcriptomic evidences

Saxena

Tiwari

Wahi³

et al. 2020

Adipocyte

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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.

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“…We next used human-derived differential expression data of adipose tissue, skeletal muscle and liver which were described in the literature in order test to which extent putative miRNA-mRNA interactions affect mRNA levels. Concerning the gWAT, we evaluated the expression of the 23 upregulated transcripts identified in gWAT of NZO mice with data of adipose tissue of 6 obese non-diabetic, 14 obese diabetic, 16 healthy and 19 diabetic patients 20,21 . Of 23 candidates which exhibit SNPs in miRNA-mRNA binding sites in the human genome, eight showed differential expression, at least in one comparison ( Supplementary Table S5).…”

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Polymorphisms in miRNA binding sites involved in metabolic diseases in mice and humans

Gottmann

Ouni

Zellner

et al. 2020

Sci Rep

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Type 2 diabetes and obesity are well-studied metabolic diseases, which are based on genetic and epigenetic alterations in combination with an obesogenic lifestyle. The aim of this study was to test whether SNPs in miRNA-mRNA binding sites that potentially disrupt binding, elevate the expression of miRNA targets, which participate in the development of metabolic diseases. A computational approach was developed that integrates transcriptomics, linkage analysis, miRNA-target prediction data, and sequence information of a mouse model of obesity and diabetes. A statistical analysis demonstrated a significant enrichment of 566 genes for a location in obesity-and diabetes-related QTL. They are expressed at higher levels in metabolically relevant tissues presumably due to altered miRNA-mRNA binding sites. Of these, 51 genes harbor conserved and impaired miRNA-mRNA-interactions in human. Among these, 38 genes have been associated to metabolic diseases according to the phenotypes of corresponding knockout mice or other results described in the literature. The remaining 13 genes (e.g. Jrk, Megf9, Slfn8 and Tmem132e) could be interesting candidates and will be investigated in the future. Obesity, the excessive accumulation of body fat, is a lifestyle-driven as well as genetically heritable disorder, and a major risk factor for secondary diseases like type 2 diabetes (T2D) 1. In the past, several studies identified candidate disease genes by human genome-wide association studies (GWAS) or linkage analysis of inbreed mouse strains 2. Most studies identified different types of variants, which lead to an impaired protein function or different regulatory effects. However, investigations with respect to genomic binding sites of other translational regulators, such as non-coding RNAs, are still in an early state for obesity and type 2 diabetes. miRNAs are small non-coding RNAs of a length of 19-24 nucleotides that alter the expression or translation of the corresponding target genes 3. The target prediction of miRNAs is still inaccurate, resulting in a high false-positive rate. The combination of different prediction tools 4 , transcriptomics 5,6 , pathway analysis and the examination of a biologically meaningful context is important to lower the false-positive rate 7. In our previous study, the validity of an integrative approach was confirmed and led to the identification of miR-31 and the elucidation of its role in adipogenesis, also showing that results obtained for mice were successfully translated to human 8. We have also demonstrated that the combination of a computational framework and a linkage analysis of several mouse strains, that differ in their diabetes susceptibility, is indeed sufficient to narrow down the critical genomic region and identify genes, which are relevant for the metabolic syndrome 9. The aim of this study was to investigate to which extent genetic variants localized in quantitative trait loci (QTL) result in a loss of miRNA-mRNA binding, thereby affecting the expression of target genes in metabolically...

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Transcriptome profiling reveals association of peripheral adipose tissue pathology with type-2 diabetes in Asian Indians

Cited by 23 publications

References 33 publications

The Transcriptomic Evidence on the Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indians Indicates the Involvement of Both

The Transcriptomic Evidence on the Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indians Indicates the Involvement of Both

The common pathophysiologic threads between Asian Indian diabetic’s ‘Thin Fat Phenotype’ and partial lipodystrophy: the peripheral adipose tissue transcriptomic evidences

Polymorphisms in miRNA binding sites involved in metabolic diseases in mice and humans

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