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Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.

van Eijk M, Aten J, Bijl N, Ottenhoff R, van Roomen CP, Dubbelhuis PF, Seeman I, Ghauharali-van der Vlugt K, Overkleeft HS, Arbeeny C, Groen AK, Aerts JM - PLoS ONE (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.c.vaneijk@amc.uva.nl

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 (Lep(Ob)) 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 Lep(Ob) 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) gamma, 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.

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Proposed mechanism of action of AMP-DNM.(A) Pathological GM3 levels inhibit insulin receptor signalling. Adipocyte dysfunction and ultimately its death results in production of inflammatory mediators, reduction of adiponectin production and spillage of lipotoxic content, which triggers macrophage activation and crown-like structure (CLS) formation. (B). Lowering of glycosphingolipids, especially GM3, restores insulin signalling, improves adipogenesis, increases adiponectin and reduces lipotoxic spillage, all leading to less inflammation and disappearance of CLS.
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pone-0004723-g006: Proposed mechanism of action of AMP-DNM.(A) Pathological GM3 levels inhibit insulin receptor signalling. Adipocyte dysfunction and ultimately its death results in production of inflammatory mediators, reduction of adiponectin production and spillage of lipotoxic content, which triggers macrophage activation and crown-like structure (CLS) formation. (B). Lowering of glycosphingolipids, especially GM3, restores insulin signalling, improves adipogenesis, increases adiponectin and reduces lipotoxic spillage, all leading to less inflammation and disappearance of CLS.

Mentions: Fig. 6 represents a model giving a possible explanation for our observations regarding the effects of glycosphingolipid lowering by AMP-DNM in adipose tissue of obese LepOb mice. AMP-DNM inhibits synthesis of glucosylceramide and subsequently GM3 formation, which results in restoration of insulin signalling. In addition, adipogenesis and adiponectin production are improved, all resulting in improved adipocyte function. As a consequence inflammation is reduced because the trigger, a dysfunctional adipocyte undergoing cell death with concomitant macrophage activation, is lost. This fits our finding of reduced numbers of crown-like structures and the reduction of the macrophage chemoattractants Ccl2 and OPN. The noted improvement in adipose tissue imposed by AMP-DNM treatment might add to the overall corrections in tissues such as muscle and liver [33].


Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.

van Eijk M, Aten J, Bijl N, Ottenhoff R, van Roomen CP, Dubbelhuis PF, Seeman I, Ghauharali-van der Vlugt K, Overkleeft HS, Arbeeny C, Groen AK, Aerts JM - PLoS ONE (2009)

Proposed mechanism of action of AMP-DNM.(A) Pathological GM3 levels inhibit insulin receptor signalling. Adipocyte dysfunction and ultimately its death results in production of inflammatory mediators, reduction of adiponectin production and spillage of lipotoxic content, which triggers macrophage activation and crown-like structure (CLS) formation. (B). Lowering of glycosphingolipids, especially GM3, restores insulin signalling, improves adipogenesis, increases adiponectin and reduces lipotoxic spillage, all leading to less inflammation and disappearance of CLS.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654925&req=5

pone-0004723-g006: Proposed mechanism of action of AMP-DNM.(A) Pathological GM3 levels inhibit insulin receptor signalling. Adipocyte dysfunction and ultimately its death results in production of inflammatory mediators, reduction of adiponectin production and spillage of lipotoxic content, which triggers macrophage activation and crown-like structure (CLS) formation. (B). Lowering of glycosphingolipids, especially GM3, restores insulin signalling, improves adipogenesis, increases adiponectin and reduces lipotoxic spillage, all leading to less inflammation and disappearance of CLS.
Mentions: Fig. 6 represents a model giving a possible explanation for our observations regarding the effects of glycosphingolipid lowering by AMP-DNM in adipose tissue of obese LepOb mice. AMP-DNM inhibits synthesis of glucosylceramide and subsequently GM3 formation, which results in restoration of insulin signalling. In addition, adipogenesis and adiponectin production are improved, all resulting in improved adipocyte function. As a consequence inflammation is reduced because the trigger, a dysfunctional adipocyte undergoing cell death with concomitant macrophage activation, is lost. This fits our finding of reduced numbers of crown-like structures and the reduction of the macrophage chemoattractants Ccl2 and OPN. The noted improvement in adipose tissue imposed by AMP-DNM treatment might add to the overall corrections in tissues such as muscle and liver [33].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.c.vaneijk@amc.uva.nl

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 (Lep(Ob)) 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 Lep(Ob) 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) gamma, 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.

Show MeSH
Related in: MedlinePlus