Adipose tissue loss and lipodystrophy in xylosyltransferase II deficient mice

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-DecreasedGAGs 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 4 Corresponding Author.

Proteoglycans in Obesity-Associated Metabolic Dysfunction and Meta-Inflammation

“…Indeed, loss of XYLT1 in humans (and mice) is associated with short-stature due to bone development issues making it difficult to assess the impact in the context of metainflammation (44). Loss of XYLT2 in mice leads to decreased AT mass and local inflammation, concomitant with decreased glucose tolerance similar to a lipodystrophy phenotype (45). Also, Xylt2-deficient mice are afflicted by multi-organ dysfunction, making it difficult to assess to what extent the observed AT dysfunction plays an exclusive role in the observed metabolic effects (45).…”

“…Loss of XYLT2 in mice leads to decreased AT mass and local inflammation, concomitant with decreased glucose tolerance similar to a lipodystrophy phenotype (45). Also, Xylt2-deficient mice are afflicted by multi-organ dysfunction, making it difficult to assess to what extent the observed AT dysfunction plays an exclusive role in the observed metabolic effects (45). Nevertheless, it is important to consider the impact of Xylt2 inactivation in diet-induced obesity.…”

Enlarged adipocytes from subcutaneous vs. visceral adipose tissue differentially contribute to metabolic dysfunction and atherogenic risk of patients with obesity

“…Nevertheless, controversial observations about the metabolic meaning of adipose tissue morphology have raised some questions; such as whether adipocyte´s size might predict metabolic health, or how small vs large adipocytes differentially contribute to metabolic dysfunction. Enlarged adipocytes are usually related to metabolic dysfunction, whereas small adipocytes are associated with metabolic benefits 15 , 16 , 20 ; however, paradoxical data have been reported in murine models: (1) adipocyte enlargement observed in SNTB2 −/− deficient mice correlates with post-prandial reduced serum glucose, glycerol and lower hepatic triglycerides 21 ; while adipocyte hypertrophy in both, SNTB2 −/− and Collagen 6 deficient mice enables a normal or improved insulin sensitivity 21 , 22 ; (2) small adipocytes described in the Xylt2 −/− deficient lipodystrophic mice associates with a metabolic profile of glucose intolerance, insulin resistance and increased serum triglycerides, as well as inflammatory infiltration of adipose tissue and higher expression of pro-inflammatory mediators 23 . Similarly, increased proportion of small adipocytes in mesenteric fat tissue is related to increased body weight, higher fat mass and decreased insulin sensitivity in the mice model of letrozole-induced polycystic ovary syndrome 24 ; and (3) non-significant effect of adipocyte size on metabolic dysfunction has been suggested by data from murine DLK1-induced decrease in adipocyte size 25 .…”

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

“…Similarly, the kidney, testis, and adrenal and thyroid glands predominant GPC5 (Fig. 4) was involved in podocyte response to injury and nephropathy progression in type 2 diabetes patients 135 and SNP was associated with acquired nephrotic syndrome, autoimmune thyroid disease, and risk for multiple sclerosis [93][94][95] . Similarly, syndecans are required for appropriate tissue response to inflammation, infection, wound healing, angiogenesis, neurological stimuli, etc.…”