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Lipodystrophy, Diabetes and Normal Serum Insulin in PPAR?-Deficient Neonatal Mice.

ABSTRACT: Peroxisome proliferator activated receptor gamma (PPAR?) is a pleiotropic ligand activated transcription factor that acts in several tissues to regulate adipocyte differentiation, lipid metabolism, insulin sensitivity and glucose homeostasis. PPAR? also regulates cardiomyocyte homeostasis and by virtue of its obligate role in placental development is required for embryonic survival. To determine the postnatal functions of PPAR? in vivo we studied globally deficient neonatal mice produced by epiblast-restricted elimination of PPAR?. PPAR?-rescued placentas support development of PPAR?-deficient embryos that are viable and born in near normal numbers. However, PPAR?-deficient neonatal mice show severe lipodystrophy, lipemia, hepatic steatosis with focal hepatitis, relative insulin deficiency and diabetes beginning soon after birth and culminating in failure to thrive and neonatal lethality between 4 and 10 days of age. These abnormalities are not observed with selective PPAR?2 deficiency or with deficiency restricted to hepatocytes, skeletal muscle, adipocytes, cardiomyocytes, endothelium or pancreatic beta cells. These observations suggest important but previously unappreciated functions for PPAR?1 in the neonatal period either alone or in combination with PPAR?2 in lipid metabolism, glucose homeostasis and insulin sensitivity.

SUBMITTER: O'Donnell PE

PROVIDER: S-EPMC4978460 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Lipodystrophy, Diabetes and Normal Serum Insulin in PPARγ-Deficient Neonatal Mice.

O'Donnell Peter E PE Ye Xiu Zhen XZ DeChellis Melissa A MA Davis Vannessa M VM Duan Sheng Zhong SZ Mortensen Richard M RM Milstone David S DS

PloS one 20160809 8

Peroxisome proliferator activated receptor gamma (PPARγ) is a pleiotropic ligand activated transcription factor that acts in several tissues to regulate adipocyte differentiation, lipid metabolism, insulin sensitivity and glucose homeostasis. PPARγ also regulates cardiomyocyte homeostasis and by virtue of its obligate role in placental development is required for embryonic survival. To determine the postnatal functions of PPARγ in vivo we studied globally deficient neonatal mice produced by epib ...[more]

PMID: 27505464

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Project description:Background/objectivesThe 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.MethodsAdipose 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.ResultsXylt2-/- 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.ConclusionsDecreased 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.

Dataset Information

Lipodystrophy, Diabetes and Normal Serum Insulin in PPAR?-Deficient Neonatal Mice.

Publications

Lipodystrophy, Diabetes and Normal Serum Insulin in PPARγ-Deficient Neonatal Mice.

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