Abstract
Adipose tissue is a critical mediator in obesity-induced insulin resistance. Previously we have demonstrated that pharmacological lowering of glycosphingolipids and subsequently GM3 by using the iminosugar AMP-DNM, strikingly improves glycemic control. Here we studied the effects of AMP-DNM on adipose tissue function and inflammation in detail to provide an explanation for the observed improved glucose homeostasis. Leptin-deficient obese (LepOb) mice were fed AMP-DNM and its effects on insulin signalling, adipogenesis and inflammation were monitored in fat tissue. We show that reduction of glycosphingolipid biosynthesis in adipose tissue of LepOb mice restores insulin signalling in isolated ex vivo insulin-stimulated adipocytes. We observed improved adipogenesis as the number of larger adipocytes was reduced and expression of genes like peroxisome proliferator-activated receptor (PPAR) γ, insulin responsive glucose transporter (GLUT)-4 and adipsin increased. In addition, we found that adiponectin gene expression and protein were increased by AMP-DNM. As a consequence of this improved function of fat tissue we observed less inflammation, which was characterized by reduced numbers of adipose tissue macrophages (crown-like structures) and reduced levels of the macrophage chemo attractants monocyte-chemoattractant protein-1 (Mcp-1/Ccl2) and osteopontin (OPN). In conclusion, pharmacological lowering of glycosphingolipids by inhibition of glucosylceramide biosynthesis improves adipocyte function and as a consequence reduces inflammation in adipose tissue of obese animals.
Highlights
Adipose tissue essentially contributes to the obesity-driven insulin resistance syndrome as it can buffer excess of energy and secretes adipokines, which control metabolic homeostasis
Fasted insulin levels and the homeostatic model assessment (HOMA) index, which is clearly increased in leptin-deficient obese (LepOb) animals, were significantly reduced upon treatment
AMP-DNM reduces macrophages in adipose tissue As we clearly observed improved adipocyte function, we investigated whether AMP-DNM treatment reduced the inflammatory status of adipose tissue in LepOb mice
Summary
Adipose tissue essentially contributes to the obesity-driven insulin resistance syndrome as it can buffer excess of energy and secretes adipokines, which control metabolic homeostasis It is not exactly understood how obesity causes this insulin resistance. Endothelial cells, adipocytes and recruited inflammatory adipose tissue macrophages (ATM) all contribute to the pro-inflammatory environment in adipose tissue of obese individuals. The presence of this ensemble is thought to promote insulin resistance [7,8,9,10,11,12,13,14]. Mice lacking a functional OPN gene, despite being obese, are insulin sensitive Their adipose tissue shows decreased macrophage infiltration and reduced inflammation
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