Adipose tissue loss and lipodystrophy in xylosyltransferase II deficient mice

Int J Obes (Lond). 2019 Sep;43(9):1783-1794. doi: 10.1038/s41366-019-0324-1. Epub 2019 Feb 18.

Abstract

Background/objectives: The cellular and extracellular matrix (ECM) interactions that regulate adipose tissue homeostasis are incompletely understood. Proteoglycans (PGs) and their sulfated glycosaminoglycans (GAGs) provide spatial and temporal signals for ECM organization and interactions with resident cells by impacting growth factor and cytokine activity. Therefore, PGs and their GAGs could be significant to adipose tissue homeostasis. The purpose of this study was to determine the role of ECM sulfated GAGs in adipose tissue homeostasis.

Methods: Adipose tissue and metabolic homeostasis in mice deficient in xylosyltransferase 2 (Xylt2-/-) were examined by histologic analyses, gene expression analyses, whole body fat composition measurements, and glucose tolerance test. Adipose tissue inflammation and adipocyte precursors were characterized by flow cytometry and in vitro culture of mesenchymal stem cells.

Results: Xylt2-/- mice have low body weight due to overall reductions in abdominal fat deposition. Histologically, the adipocytes are reduced in size and number in both gonadal and mesenteric fat depots of Xylt2-/- mice. In addition, these mice are glucose intolerant, insulin resistant, and have increased serum triglycerides as compared to Xylt2 + / + control mice. Furthermore, the adipose tissue niche has increased inflammatory cells and enrichment of proinflammatory factors IL6 and IL1β, and these mice also have a loss of adipose tissue vascular endothelial cells. Lastly, xylosyltransferease-2 (XylT2) deficient mesenchymal stem cells from gonadal adipose tissue and bone marrow exhibit impaired adipogenic differentiation in vitro.

Conclusions: Decreased GAGs due to the loss of the key GAG assembly enzyme XylT2 causes reduced steady state adipose tissue stores leading to a unique lipodystrophic model. Accumulation of an adipocytic precursor pool of cells is discovered indicating an interruption in differentiation. Therefore, adipose tissue GAGs are important in the homeostasis of adipose tissue by mediating control of adipose precursor development, tissue inflammation, and vascular development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue* / chemistry
  • Adipose Tissue* / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / physiology
  • Cytokines / metabolism
  • Extracellular Matrix / chemistry
  • Female
  • Glycosaminoglycans / chemistry
  • Glycosaminoglycans / metabolism
  • Lipodystrophy / genetics
  • Lipodystrophy / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Pentosyltransferases* / deficiency
  • Pentosyltransferases* / genetics
  • Pentosyltransferases* / metabolism
  • Pentosyltransferases* / physiology

Substances

  • Blood Glucose
  • Cytokines
  • Glycosaminoglycans
  • Pentosyltransferases
  • UDP xylose-protein xylosyltransferase