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  • To validate a role for Prg

    2019-07-24

    To validate a role for Prg4 in the white adipose tissue of obese humans, we checked Prg4 gene expression in a cohort of obese women with and without type 2 diabetes. Type 2 diabetic women had increased expression of Prg4 in subcutaneous white adipose tissue as compared to normoglycemic controls. However, this was not mirrored in the omental adipose tissue depot. It is known that adipose depots are functionally different based on their location [34]. The subcutaneous adipose tissue of obese women has increased capacity to take up circulating fatty acids as indicated by an increased lipoprotein lipase expression as compared to the omental adipose tissue depot [34]. Furthermore, the subcutaneous adipose tissue depot acts systemically to regulate glucose homeostasis in contrast to omental adipose tissue [35]. So the differentially expressed Prg4 might partially underlie these functional differences between the subcutaneous and omental adipose. Our observation that Prg4 expression levels in mouse liver were significantly altered (increased) in response to HFD feeding while those in murine gonadal white adipose tissue remained unaltered further supports the concept of functional tissue-specificity. These combined data suggest that Prg4 not only in mice, but also in humans plays a role in nutritional homeostasis. To date, the metabolic function of Prg4 is unknown. Prg4 is ubiquitously expressed and secreted into the circulation. From our previous studies in the context of atherosclerosis, it has become apparent that systemic depletion of Prg4 levels is causally related to an increased atherosclerosis susceptibility [36]. However, Prg4 can also have local effects as judged from the finding that Prg4 produced locally by macrophages can affect the functionality of these Moniliformin [37,38]. Prg4 KO mice show an improved metabolic phenotype of the liver, muscle and white adipose tissue. These effects could be mediated via independent actions in these organs or via one central pathway. Interestingly, several genes that are regulated by insulin are differentially expressed in Prg4 KO mice as compared to WT mice. Genes in the glycolysis and lipogenesis pathways in the liver as well as genes involved in glucose metabolism in the muscle and genes in the white adipose tissue are all less activated. Further insight in the insulin signaling pathway in Prg4 KO mice might elucidate whether there is a common underlying mechanism. We have shown that the gene expression levels of Prg4 are highest in the liver and that these levels are changed in response to a HFD challenge. The liver is also the organ where we found the most pronounced effects of Prg4 deficiency. Proteoglycans play a role in the cellular uptake of lipids from the circulation [39,40] and the clearance of remnant lipoproteins in the liver [41,42]. Olsson and colleagues found that both insulin and circulating fatty acids can alter the structure of secreted proteoglycans by the liver [43]. This structural change affected the capacity of hepatic proteoglycans to clear remnants of triglyceride-rich lipoproteins from the circulation, augmenting the dyslipidemia in insulin-resistant rodents [43]. Although it seemed that the absence of Prg4 had profound effects on plasma lipid levels and hepatic lipogenesis, the uptake of the fatty acids derived from the VLDL-like particles labeled with glycerol tri[3H]oleate from the circulation was not significantly changed in our experimental setup. Specific studies tracking the cholesterol component of VLDL-like particles will be needed to provide more insight in a potential role of Prg4 in the uptake of the remnants by the liver. Interestingly, Prg4 was recently identified as a specific marker for the pancreatic delta and pancreatic polypeptide cell subsets, which only comprise 3–15% of the cell population present in the islets of Langerhans [44,45]. The islets of Langerhans are clusters of endocrine cells that are affected in the pathology of diabetes. The islets consist of four main cell subsets, which closely work together in a paracrine fashion, regulating blood glucose by secreting insulin, glucagon and somatostatin [7,8]. Prg4 was one of the most differentially expressed genes in the pancreas of diabetic individuals versus healthy human controls [6]. Given the improved glucose handling in Prg4 KO mice and the contribution of the pancreas to the control of total body glucose metabolism, it would be highly interesting to perform further studies to elucidate the function of Prg4 in these cells. It could be proposed that Prg4, as one of the proteoglycans in the extracellular matrix, contributes to the interactions between islet cells and the extracellular matrix and therefore is essential for islet functionality [46]. Furthermore, intracellular proteoglycans are involved in the storage of secretory granules and the delivery and modulation of activity of the content of secretory granules in different cell types including hematopoietic cell types, pancreatic acinar cells and platelets [47,48]. Since the islets of Langerhans are specialized in the production and secretion of a range of hormones including insulin, glucagon and somatostatin, it can be proposed that Prg4 is involved in the functioning of the secretory vesicles that contain these products.