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

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 adipo...

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Autores principales:	Marco van Eijk, Jan Aten, Nora Bijl, Roelof Ottenhoff, Cindy P A A van Roomen, Peter F Dubbelhuis, Ingar Seeman, Karen Ghauharali-van der Vlugt, Hermen S Overkleeft, Cynthia Arbeeny, Albert K Groen, Johannes M F G Aerts
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4de7292dc62c4bccba10a1b9b8fc6b87
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spelling	oai:doaj.org-article:4de7292dc62c4bccba10a1b9b8fc6b872021-11-25T06:16:32ZReducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.1932-620310.1371/journal.pone.0004723https://doaj.org/article/4de7292dc62c4bccba10a1b9b8fc6b872009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19305508/?tool=EBIhttps://doaj.org/toc/1932-6203Adipose 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.Marco van EijkJan AtenNora BijlRoelof OttenhoffCindy P A A van RoomenPeter F DubbelhuisIngar SeemanKaren Ghauharali-van der VlugtHermen S OverkleeftCynthia ArbeenyAlbert K GroenJohannes M F G AertsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 3, p e4723 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marco van Eijk Jan Aten Nora Bijl Roelof Ottenhoff Cindy P A A van Roomen Peter F Dubbelhuis Ingar Seeman Karen Ghauharali-van der Vlugt Hermen S Overkleeft Cynthia Arbeeny Albert K Groen Johannes M F G Aerts Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
description	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.
format	article
author	Marco van Eijk Jan Aten Nora Bijl Roelof Ottenhoff Cindy P A A van Roomen Peter F Dubbelhuis Ingar Seeman Karen Ghauharali-van der Vlugt Hermen S Overkleeft Cynthia Arbeeny Albert K Groen Johannes M F G Aerts
author_facet	Marco van Eijk Jan Aten Nora Bijl Roelof Ottenhoff Cindy P A A van Roomen Peter F Dubbelhuis Ingar Seeman Karen Ghauharali-van der Vlugt Hermen S Overkleeft Cynthia Arbeeny Albert K Groen Johannes M F G Aerts
author_sort	Marco van Eijk
title	Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
title_short	Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
title_full	Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
title_fullStr	Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
title_full_unstemmed	Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
title_sort	reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/4de7292dc62c4bccba10a1b9b8fc6b87
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Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.

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