Abstract
Pancreatic steatosis associates with β-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.
Highlights
Obesity, defined as an excess accumulation of white adipose tissue (WAT) mass, is a global health concern that is linked to an increased risk for metabolic perturbations such as type-2-diabetes (T2D), cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD) [1]
Comparative transcriptome analysis of 26,735 expressed transcripts revealed 1,456 differentially expressed transcripts referring to 1227 genes (DEGs) with 757 significantly up- and 699 significantly downregulated genes in pancreas MSCs (pMSC) compared to iwatMSCs (Figure 2A)
Gene ontology (GO) enrichment analysis allocated differentially expressed genes (DEGs) to 15 significant biological processes (Figure 2B), of which most were assigned to positive regulation of developmental processes and fat cell differentiation, cell adhesion, cell migration, and others involving re-arrangement of the cytoskeleton
Summary
Obesity, defined as an excess accumulation of white adipose tissue (WAT) mass, is a global health concern that is linked to an increased risk for metabolic perturbations such as type-2-diabetes (T2D), cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD) [1]. Excessive levels of circulating lipids combined with a limited adipocyte storage capacity result in ectopic fat accumulation in non-adipose tissue organs such as liver and muscle, taking the shape of intra-hepatocyte and intra-myocyte lipid droplet stores or as bona fide mature adipocytes interspersed within bone tissue, and the pancreas [4,5,6,7,8]. These ectopic lipid depositions are linked to organ dysfunction, insulin resistance, and the predisposition to develop T2D [4,8]. There is growing evidence that NAFPD plays a substantial role in human pancreatic fibrosis, pancreatic cancer, and β-cell dysfunction [11]
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