Novel genes and cellular pathways related to infection with adenovirus-36 as an obesity agent in human mesenchymal stem cells

Abstract

Objective: The objective of this study was to investigate the molecular mechanisms underlying adenovirus-36 (Ad-36)-induced obesity by the identification of novel genes and cellular pathways. Design: Viral growth, intracellular lipid accumulation and gene expression profiles were determined in human mesenchymal stem cells (hMSCs) infected with Ad-36 or Ad-2. A microarray assay and gene set enrichment analysis (GSEA) were performed to assess alterations in global gene expression profiles. Results: Ad-36, but not Ad-2, induced lipid accumulation and upregulated adipogenesis-related genes. There was no difference in viral growth between Ad-36 infection and Ad-2 infection in hMSCs. GSEA revealed that Ad-36 infection was more frequently associated with activation of novel pathways, including the PPAR-gamma signaling pathway, and inflammation compared with Ad-2 infection, raising the possibility that these pathways may be key regulators of Ad-36-induced adipogenesis. Conclusion: This study may help foster a better understanding of the roles of several cellular factors in Ad-36-induced obesity.

Possible Association of Altered Serum Lipids in Obese Adult Females with Adenoviral Infection

“…The most important limitation was using an non-specific ELISA test which provide a measurement of the total anti-adenovirus antibody level, so the results of our study can not explain which serotype of adenovirus is connected with alternations in serum lipid levels. Whereas, the impact of adenovirus serotype differences in changes of serum lipid levels in obese humans have been reported earlier [17,37,40,48].…”

“…Ad-36 related hypothalamus damage or Ad-36 linked altering of adipocyte differentiation, are involved to increase adiposity and serum lipid changes in obese humans with positive antibody status to Ad-36 adenovirus. However, recently the role of upregulated adipogenesis-related genes and activation of peroxisome proliferator-activated receptors PPAR-signaling pathway in the Ad-36 induced lipid accumulation by human mesenchymal stem cells have been postulated on the results of microarray assay and gene set enrichment analysis [48]. In addition, the significance of the increased oxidative stress condition in the mechanism of adenovirus infection related obesity have been suggested in the currently published report [49].…”

Harnessing the beneficial properties of adipogenic microbes for improving human health

“…Ad36 was shown to stimulate the Ras pathway, thereby leading to excess glucose transport into cells, particularly fat cells (60). Also, fatty acid synthase (FAS) is stimulated by the virus, and the combination of excess substrate (glucose) and FAS results in excess fat deposition in adipocytes and other human cell lines (12,16,23,24,(60)(61)(62)(63)(64)(65)(66)(67)(68)(69). Thus, Ad36 was thought to produce obesity by acting directly on adipocytes (inducing de novo lipogenesis).…”

Is obesity caused by an adenovirus?

“…Animals excrete Ad-36 in feces for up to 2 months postinfection [11] and the virus seems to quickly reach multiple organs, including the liver, spleen, kidney, brain and, surprisingly, the adipose tissue [17]. The amount of Ad-36 DNA present in the adipose tissue significantly correlates with adipose tissue mass of that animal [8], which led the way to discovering the role of adipocyte differentiation as a potential mechanism for Ad-36-induced obesity [18][19][20][21][22]. MCP-1 and E4orf1, appear to be the required host and viral factors, respectively, for Ad-36-induced adiposity [23,24].…”

“…Ad-36 improves high-fat diet-induced hyperglycemia and hepatic steatosis, and reduces serum cholesterol and triglyceride levels, despite the adiposity it induces [8][9][10][11]16]. Findings from several studies indicate that via its E4orf1 gene, Ad-36 induces adipogenic commitment, proliferation and lipid accumulation in adipocyte progenitors, and also increases cellular glucose and lipid uptake [16,[18][19][20][22][23][24][25][26][27]. Collectively, these effects appear to explain adipose tissue expansion and a paradoxical clearance of lipids and glucose levels from the circulation induced by Ad-36.…”