Rosiglitazone Enhances Browning Adipocytes in Association with MAPK and PI3-K Pathways During the Differentiation of Telomerase-Transformed Mesenchymal Stromal Cells into Adipocytes

Obesity is a major risk for diabetes. Brown adipose tissue (BAT) mediates production of heat while white adipose tissue (WAT) function in the storage of fat. Roles of BAT in the treatment of obesity and related disorders warrants more investigation. Peroxisome proliferator activator receptor gamma (PPAR-γ) is the master regulator of both BAT and WAT adipogenesis and has roles in glucose and fatty acid metabolism. Adipose tissue is the major expression site for PPAR-γ. In this study, the effects of rosiglitazone on the brown adipogenesis and the association of MAPK and PI3K pathways was investigated during the in vitro adipogenic differentiation of telomerase transformed mesenchymal stromal cells (iMSCs). Our data indicate that 2 µM rosiglitazone enhanced adipogenesis by over-expression of PPAR-γ and C/EBP-α. More specifically, brown adipogenesis was enhanced by the upregulation of EBF2 and UCP-1 and evidenced by multilocular fatty droplets morphology of the differentiated adipocytes. We also found that rosiglitazone significantly activated MAPK and PI3K pathways at the maturation stage of differentiation. Overall, the results indicate that rosiglitazone induced overexpression of PPAR-γ that in turn enhanced adipogenesis, particularly browning adipogenesis. This study reports the browning effects of rosiglitazone during the differentiation of iMSCs into adipocytes in association with the activation of MAPK and PI3K signaling pathways.

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The Suv420h histone methyltransferases regulate PPAR-γ and energy expenditure in response to environmental stimuli

Science Advances ◽

10.1126/sciadv.aav1472 ◽

2019 ◽

Vol 5 (4) ◽

pp. eaav1472 ◽

Cited By ~ 3

Author(s):

Simona Pedrotti ◽

Roberta Caccia ◽

Maria Victoria Neguembor ◽

Jose Manuel Garcia-Manteiga ◽

Giulia Ferri ◽

...

Keyword(s):

Adipose Tissue ◽

Molecular Mechanisms ◽

Target Genes ◽

Ex Vivo ◽

Peroxisome Proliferator ◽

Histone Methyltransferases ◽

Environmental Stimuli ◽

Ppar Γ ◽

Brown Adipose

Obesity and its associated metabolic abnormalities have become a global emergency with considerable morbidity and mortality. Epidemiologic and animal model data suggest an epigenetic contribution to obesity. Nevertheless, the cellular and molecular mechanisms through which epigenetics contributes to the development of obesity remain to be elucidated. Suv420h1 and Suv420h2 are histone methyltransferases responsible for chromatin compaction and gene repression. Through in vivo, ex vivo, and in vitro studies, we found that Suv420h1 and Suv420h2 respond to environmental stimuli and regulate metabolism by down-regulating peroxisome proliferator–activated receptor gamma (PPAR-γ), a master transcriptional regulator of lipid storage and glucose metabolism. Accordingly, mice lacking Suv420h proteins activate PPAR-γ target genes in brown adipose tissue to increase mitochondria respiration, improve glucose tolerance, and reduce adipose tissue to fight obesity. We conclude that Suv420h proteins are key epigenetic regulators of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.

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The lower in vitro chondrogenic potential of canine adipose tissue-derived mesenchymal stromal cells (MSC) compared to bone marrow derived MSC is not improved by BMP-2 or BMP-6

The Veterinary Journal ◽

10.1016/j.tvjl.2020.105605 ◽

2020 ◽

pp. 105605

Author(s):

M. Teunissen ◽

F. Verseijden ◽

F.M. Riemers ◽

G.J.V.M. van Osch ◽

M.A. Tryfonidou

Keyword(s):

Bone Marrow ◽

Adipose Tissue ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Chondrogenic Potential

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Periostin expression and characters of human adipose tissue-derived mesenchymal stromal cells were aberrantly affected by in vitro cultivation

Stem Cell Investigation ◽

10.21037/sci.2019.08.09 ◽

2019 ◽

Vol 6 ◽

pp. 33-33 ◽

Cited By ~ 2

Author(s):

Heba M. Saad Eldien ◽

Hekmat Osman Abdel-Aziz ◽

Douaa Sayed ◽

Wafaa Mubarak ◽

Hemmat H. G. Hareedy ◽

...

Keyword(s):

Adipose Tissue ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Human Adipose Tissue ◽

In Vitro Cultivation

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mRNA expression of genes related to fat deposition during in vitro ovine adipogenesis

Canadian Journal of Animal Science ◽

10.1139/cjas-2018-0107 ◽

2019 ◽

Vol 99 (4) ◽

pp. 764-771 ◽

Cited By ~ 1

Author(s):

Baojun Li ◽

Liying Qiao ◽

Xiaoru Yan ◽

Tao Shi ◽

Duanyang Ren ◽

...

Keyword(s):

Mrna Expression ◽

Binding Protein ◽

Adipogenic Differentiation ◽

Fat Deposition ◽

Peroxisome Proliferator ◽

Induced Differentiation ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

Ppar Γ

Fat deposition in animals involves adipogenic differentiation guided by transcriptional factors and other key factors. To understand the molecular mechanism underlying ovine adipogenic differentiation, the dynamic mRNA expression of key genes related to fat deposition, including peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid-binding protein 4 (FABP4), FABP5, and cellular retinoic acid-binding protein 2 (CRABP2), were analyzed during in vitro differentiation of ovine preadipocytes. The stromal vascular cells from underneath the tail fat tissue of 1-wk-old sheep were isolated and cultured, and the preadipocytes were induced using a cocktail of 3-isobutyl-1-methylxanthine, insulin, dexamethasone, and troglitazone. The cultivated cells were collected at different time points after induced differentiation. The expression levels of PPAR-γ, FABP4, FABP5, and CRABP2 were studied by quantitative real-time polymerase chain reaction. The expressions of these genes in sheep were compared with those in human and mouse retrieved from the Gene Expression Omnibus DataSets. We observed that the expression of PPAR-γ, FABP4, and FABP5 was increased upon differentiation of ovine preadipocytes, as in humans and mice. The expression of CRABP2 was sharply increased from days 0 to 2 after induced differentiation and was subsequently decreased. This expression pattern of CRABP2 was different from that observed in humans and mice. Our results provide new insights into the function of these genes in fat deposition.

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Lenalidomide Modulates the Phenotype and Function of Human Mesenchymal Stromal Cells From Healthy Donors and MDS Patients.

Blood ◽

10.1182/blood.v114.22.3816.3816 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3816-3816

Author(s):

Manja Wobus ◽

Gwendolin Dünnebier ◽

Silvia Feldmann ◽

Gerhard Ehninger ◽

Martin Bornhauser ◽

...

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Clinical Efficacy ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Morphological Changes ◽

Adipogenic Differentiation ◽

Healthy Controls ◽

Healthy Donors

Abstract Abstract 3816 Poster Board III-752 Introduction Recent studies in patients with MDS have clearly demonstrated the clinical efficacy of lenalidomide. However, its exact mechanisms of action have not been elucidated yet. Myelosuppression is the most common adverse event and seems to be dependent on dose as well MDS subtype, being rather infrequent in patients other than del5q. The aim of this study was to investigate whether lenalidomide affects the bone marrow microenvironment. Therefore, we analyzed in-vitro characteristics of isolated mesenchymal stromal cells (MSCs) from MDS patients and from healthy controls. Methods Bone marrow samples were collected from healthy donors (n=5) and patients with MDS (del5q MDS n=3, RA n=2, RAEB1/2 n=3). MSCs were isolated according to the standard adhesion protocol and cultured in the presence or absence of lenalidomide. Results Lenalidomide treatment of MSCs caused no morphological changes but proliferation was slightly increased. Typical surface molecules as CD73, CD90, CD105 and CD166 were expressed in MSCs from MDS patients at comparable levels to healthy controls. Lenalidomide treatment caused an upregulation of CD29 by 17.8 ± 4.4% and of CD73 by 24 ± 5.7% (mean fluorescence intensity). Investigating the cytokine production, we found lower IL-8 mRNA and protein levels in MSCs from MDS patients (mean in MDS MSC: 138.1 pg/ml vs. mean in healthy MSC: 1177 pg/ml). Interestingly, the IL-8 production can be increased by approximately 40% under lenalidomide treatment. MDS MSCs retained the capacity for adipogenic and osteogenic differentiation as well as their supportive function towards hematopoietic cells in long term culture-initiating assays (LTC-IC). However, the LTC-IC frequency was lower on MSC which had been preincubated with lenalidomide compared to controls. Lenalidomide also slightly accelerated osteogenic differentiation because mineralization started as early as on day 5 with lenalidomide whereas in the control cells first calcium deposits were visible after 7 days. Other samples showed augmented lipid vacuoles after adipogenic differentiation under lenalidomide treatment. Conclusion In conclusion, lenalidomide modulates the phenotype of MSC and leads to an increase of their IL-8 secretion by a yet unknown mechanism. Whether these in-vitro effects are associated with the clinical efficacy of this compound in patients with MDS remains to be investigated. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Expression of peroxisome proliferator-activated receptors in lean and obese Zucker rats

Acta Endocrinologica ◽

10.1530/eje.0.1420071 ◽

2000 ◽

pp. 71-78 ◽

Cited By ~ 29

Author(s):

A Gorla-Bajszczak ◽

C Siegrist-Kaiser ◽

O Boss ◽

AG Burger ◽

CA Meier

Keyword(s):

Adipose Tissue ◽

Fiber Type ◽

Zucker Rats ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Rnase Protection ◽

Brown Adipose ◽

Obese Zucker Rats

OBJECTIVE: Examination of the pattern of expression of peroxisome proliferator-activated receptor (PPAR) isoforms alpha and gamma in a model of obesity. DESIGN: Examination of adipose tissue and primary adipocyte cultures from lean and obese Zucker rats at different ages (28 days and 12 weeks). METHODS: mRNA levels were measured by RNase protection assay.RESULTS: The highest levels of PPARalpha and gamma mRNA were present in brown adipose tissue (BAT), followed by liver and white adipose tissue (WAT) for the alpha and gamma subtypes, respectively, at both ages examined. PPARalpha was expressed 100-fold higher in BAT compared with WAT, and PPARgamma mRNA levels were 2-fold higher in the WAT of obese compared with lean rats. PPARalpha and gamma expression was minimal in m. soleus, although higher levels of PPARgamma were found in the diaphragm. In marked contrast to the findings in vivo, virtually no PPARalpha mRNA could be detected in BAT cultures differentiated in vitro. CONCLUSION: PPARalpha and gamma are most highly expressed in BAT in vivo. However, PPARalpha is undetectable in brown adipose cells in vitro, suggesting that the expression of this receptor is induced by some external stimuli. In addition, the expression of PPARgamma was increased in WAT from young obese animals, compatible with an early adaptive phenomenon. Finally, the presence of PPARgamma mRNA is detectable only in particular muscles, such as the diaphragm, suggesting the possibility of an influence of fiber type on its expression, although exercise did not influence the expression of PPARgamma in other skeletal muscles.

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