Peroxisome Proliferator-Activated Receptor-γPromotes Adipogenic Changes in Growth Plate Chondrocytes In Vitro

Chondrocytes and adipocytes are two differentiated cell types which are both derived from mesenchymal cells. The purpose of this study was to investigate whether peroxisome proliferator-activated receptor-γ(PPARγ), a transcription factor involved in lineage determination during adipogenesis, is able to induce adipogenic differentiation in growth plate chondrocytes. Isolated epiphyseal chondrocytes were infected with a PPARγadenovirus or treated with the PPARγagonist ciglitazone. Both of these treatments resulted in lipid droplet accumulation and expression of the adipogenic markers aP2, lipoprotein lipase, and adipsin in chondrocytes. Proteoglycan matrix synthesis was decreased in the PPARγ-infected cells, as was the expression of the chondrogenic genes Col2a1 and aggrecan. Growth plate cells transfected with a PPARγexpression plasmid under the control of the collagenα1(II) promoter also demonstrated a similar adipogenic changes. Terminal differentiation of growth plate chondrocytes induced by thyroid hormone was also inhibited by overexpression of PPARγand ciglitazone treatment, with decreased expression of alkaline phosphatase and Runx2/Cbfa1 genes. These in vitro data suggest that PPARγis able to promote adipogenic differentiation in growth plate chondrocytes, while negatively regulating chondrogenic differentiation and terminal differentiation.

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Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Audiology and Neurotology ◽

10.1159/000506796 ◽

2020 ◽

Vol 25 (6) ◽

pp. 297-308

Author(s):

Maurizio Cortada ◽

Eric Wei ◽

Neha Jain ◽

Soledad Levano ◽

Daniel Bodmer

Keyword(s):

Hair Cells ◽

Cell Types ◽

Protective Role ◽

Angiotensin Ii Receptor Blocker ◽

Peroxisome Proliferator ◽

Angiotensin Ii Receptor ◽

Peroxisome Proliferator Activated Receptor ◽

Auditory Hair Cells ◽

Ppar Γ

Background: Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. Objectives: The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. Methods: Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. Results: Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. Conclusions: We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.

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Physiological Functions of Peroxisome Proliferator-Activated Receptor β

Physiological Reviews ◽

10.1152/physrev.00027.2013 ◽

2014 ◽

Vol 94 (3) ◽

pp. 795-858 ◽

Cited By ~ 89

Author(s):

Jaap G. Neels ◽

Paul A. Grimaldi

Keyword(s):

Therapeutic Option ◽

Cell Types ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

In Vivo Models ◽

Physiological Functions ◽

Regulatory Pathways ◽

Inflammatory Conditions

The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.

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THE EFFECT OF A SLIGHTLY ACIDIC SOMATOMEDIN PEPTIDE (ILAs) ON THE SULPHATION OF PROTEOGLYCANS FROM ARTICULAR AND GROWTH PLATE CHONDROCYTES IN CULTURE

Acta Endocrinologica ◽

10.1530/acta.0.0890263 ◽

1978 ◽

Vol 89 (2) ◽

pp. 263-275 ◽

Cited By ~ 21

Author(s):

Marie-Thérèse Corvol ◽

Marie-France Dumontier ◽

Raphael Rappaport ◽

Harvey Guyda ◽

Barry I. Posner

Keyword(s):

Growth Plate ◽

Deae Cellulose ◽

Morphological Characteristics ◽

Cell Types ◽

Epiphyseal Growth Plate ◽

Growth Plate Chondrocytes ◽

Electrophoretic Patterns ◽

Agarose Electrophoresis ◽

Well Differentiated

ABSTRACT Chondrocyte cultures were prepared from rabbit growth plate (GPC) and articular (ARC) chondrocytes. These two cell types have distinct morphological characteristics. The cells reached maximum numbers by days 10 and 21 for ARC and GPC, respectively. The proteoglycans (PG) contained in the cellular pool were extracted and purified by DEAE cellulose chromatography. The effect of a partially purified somatomedin peptide with insulin-like activity on [35S] sulphate incorporation into PG was evaluated. In both ARC and GPC a significant stimulation of [35S]sulphate uptake into PG subunits was obtained with 1 ng Eq./ml of somatomedin peptide. In order to obtain the same stimulatory effect with porcine insulin, a 1000-fold greater concentration was required. The electrophoretic patterns of the PG subunits on acrylamide-agarose electrophoresis were identical on control incubations and after stimulation with the somatomedin peptide. These data demonstrate in vitro biological activity of this peptide on well differentiated articular and epiphyseal growth plate chondrocytes in culture. These cultures appear to provide a sensitive biological assay for somatomedin peptides.

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Interferon-Stimulated Gene ISG12b1 Inhibits Adipogenic Differentiation and Mitochondrial Biogenesis in 3T3-L1 Cells

Endocrinology ◽

10.1210/en.2008-0727 ◽

2008 ◽

Vol 150 (3) ◽

pp. 1217-1224 ◽

Cited By ~ 21

Author(s):

Bing Li ◽

Jonghyun Shin ◽

Kichoon Lee

Keyword(s):

Mitochondrial Biogenesis ◽

Adipogenic Differentiation ◽

Peroxisome Proliferator ◽

Mitochondrial Transcription ◽

Peroxisome Proliferator Activated Receptor ◽

And Function ◽

Adipocyte Development

Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer-binding protein-α (C/EBPα). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARγ and PPARα agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases. ISG12b1 is predominantly expressed in adipocytes and dramatically induced at the terminal stage of adipogenesis. Functionally, mitochondria-localized ISG12b1 inhibits adipogenic differentiation and mitochondria biogenesis.

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Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways

AJP Cell Physiology ◽

10.1152/ajpcell.00331.2001 ◽

2002 ◽

Vol 282 (4) ◽

pp. C853-C863 ◽

Cited By ~ 95

Author(s):

F. Machinal-Quélin ◽

M. N. Dieudonné ◽

M. C. Leneveu ◽

R. Pecquery ◽

Y. Giudicelli

Keyword(s):

Subcutaneous Fat ◽

Cell Types ◽

Binding Activity ◽

Mitogen Activated Protein Kinase ◽

Cell Counting ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Stat3 Phosphorylation

Because leptin has recently been shown to induce proliferation and/or differentiation of different cell types through different pathways, the aim of the present study was to investigate, in vitro, the influence of leptin on adipogenesis in rat preadipocytes. A prerequisite to this study was to identify leptin receptors (Ob-Ra and Ob-Rb) in preadipocytes from femoral subcutaneous fat. We observed that expressions of Ob-Ra and Ob-Rb increase during adipogenesis. Furthermore, leptin induces an increase of p42/p44 mitogen-activated protein kinase phosphorylated isoforms in both confluent and differentiated preadipocytes and of STAT3 phosphorylation only in confluent preadipocytes. Moreover, exposure to leptin promoted activator protein-1 complex DNA binding activity in confluent preadipocytes. Finally, exposure of primary cultured preadipocytes from the subcutaneous area to leptin (10 nM) resulted in an increased proliferation ([3H]thymidine incorporation and cell counting) and differentiation (glycerol-3-phosphate dehydrogenase activity and mRNA levels of lipoprotein lipase, peroxisome proliferator-activated receptor-γ2, and c-fos). Altogether, these results indicate that, in vitro at least, leptin through its functional receptors exerts a proadipogenic action in subcutaneous preadipocytes.

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Estrogen receptor mediates the effects of pseudoprotodiocsin on adipogenesis in 3T3-L1 cells

AJP Cell Physiology ◽

10.1152/ajpcell.00538.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. C128-C138 ◽

Cited By ~ 28

Author(s):

Jing Xiao ◽

Nai-li Wang ◽

Bing Sun ◽

Guo-ping Cai

Keyword(s):

Leucine Zipper ◽

Binding Protein ◽

Adipogenic Differentiation ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Underlying Mechanisms

Estrogen receptors (ERs) play a pivotal role in adipogenesis; therefore, compounds targeting ERs may also affect fat formation. Recent studies have shown that the Dioscorea plant (commonly called yam) exhibits an antiobesity effect on rodents. However, the active compounds and underlying mechanisms responsible for this effect are not yet fully understood. We evaluated the effects of pseudoprotodiocsin (PPD), a steroid saponin from Dioscorea nipponica Makino (a type of Dioscorea), on adipogenesis and the mechanisms underlying this effect. Treatment with PPD at the onset of adipogenic differentiation resulted in significantly decreased adipogenesis in both in vitro and in vivo experimental systems. An increased amount of ERα mRNA, protein, and the accumulation of ERα in the nucleus were also observed. However, the expression pattern of ERβ was not altered. Furthermore, the antiadipogenic effect of PPD was found to be ER dependent. It was also accompanied by the decreased expression of several genes involved in adipogenesis, including lipoprotein lipase (LPL), leptin, CCAAT/enhancer-binding-protein-α (C/EBPα), and peroxisome proliferator-activated receptor-γ (PPARγ), as well as the increased expression of some negative factors of adipogenesis, including preadipocyte factor 1 (Pre-1), GATA-binding protein 2 (GATA-2), GC-induced leucine-zipper protein (GILZ), and C/EBP homologous protein (CHOP-10). In addition to its estrogenic action, PPD also abolished the p38 mitogen-activated protein kinase (p38 MAPK) activation. Our results suggest that PPD inhibits adipogenesis in an ER-dependent manner and induces the expression of ERα. These findings may provide a lead toward a novel agent that can be used to treat obesity.

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Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

Scientifica ◽

10.1155/2013/684736 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 151

Author(s):

Aaron W. James

Keyword(s):

Transcription Factors ◽

Signaling Pathways ◽

Hedgehog Signaling ◽

Adipogenic Differentiation ◽

Cell Types ◽

Bmp Signaling ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Growth Factor ◽

Related Transcription Factor

Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ(PPARγ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPARγand Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These includeβ-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

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Antiadipogenesis and Osseointegration of Strontium-Doped Implant Surfaces

Journal of Dental Research ◽

10.1177/0022034519850574 ◽

2019 ◽

Vol 98 (7) ◽

pp. 795-802 ◽

Cited By ~ 2

Author(s):

C. Zhou ◽

Y.Q. Chen ◽

Y.H. Zhu ◽

G.F. Lin ◽

L.F. Zhang ◽

...

Keyword(s):

Adipogenic Differentiation ◽

Hydrothermal Process ◽

Inhibitory Effect ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Peroxisome Proliferator Activated Receptor ◽

Dental Implantation ◽

Gene And Protein Expression ◽

Initial Adhesion

The decreased bone density and increased marrow adiposity that occur with aging may influence the outcome of dental implants. Strontium (Sr), an anabolic agent for the treatment of osteoporosis, has an inhibitory effect on adipogenesis but favors osteogenesis of bone marrow–derived mesenchymal stem cells (BMSCs). However, little is known about the effects and mechanisms of local Sr release on adipogenesis during bone formation in aged bone. In this study, a potential dental implant material, Sr-doped titanium, was developed via a sandblasted, large-grit, and acid-etched (SLA) method combined with a hydrothermal process. The effects of Sr-SLA on initial adhesion, proliferation, intracellular redox state, and adipogenic differentiation of senescent BMSCs were investigated. The in vitro results showed that Sr-SLA promoted spreading of senescent BMSCs via upregulation of the gene and protein expression of integrin β1. In addition, it was revealed that Sr-SLA could reduce intracellular oxidative stress by decreasing the levels of reactive oxygen species and oxygen radicals and increasing the content of glutathione peroxidase. More important, Sr-SLA suppressed lipid droplet production and adipokines expression via downregulation of transcription peroxisome proliferator-activated receptor γ (PPARγ) and signal transducer and activator of transcription 1, thus inhibiting adipogenesis. Finally, the Sr-SLA implants were implanted in tibiae of aged (18-mo-old) Sprague-Dawley rats for 2 and 8 wk. Histomorphometric analysis demonstrated that Sr-SLA implants significantly enhanced osseointegration, and the inhibition effect on marrow adipose tissue formation was moderate. All these results suggest that due to the multiple functions produced by Sr, antiadipogenesis capability and rapid osseointegration were enhanced by the Sr-SLA coatings, which have potential application in dental implantation in the aged population.

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Leptin Antagonizes Peroxisome Proliferator-Activated Receptor-γSignaling in Growth Plate Chondrocytes

PPAR Research ◽

10.1155/2012/756198 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 10

Author(s):

Lai Wang ◽

Yvonne Y. Shao ◽

R. Tracy Ballock

Keyword(s):

Growth Plate ◽

Chondrogenic Differentiation ◽

Erk Signaling ◽

Peroxisome Proliferator ◽

Newborn Rats ◽

Inhibitory Effects ◽

Growth Plate Chondrocytes ◽

Peroxisome Proliferator Activated Receptor ◽

Proliferation And Differentiation

Leptin is an obesity-associated cytokine-like hormone encoded by theobgene. Recent studies reveal that leptin promotes proliferation and differentiation of chondrocytes, suggesting a peripheral role of leptin in regulating growth plate function. Peroxisome proliferator-activated receptor-γ(PPARγ) is a transcriptional regulator of adipogenesis. Locally, PPARγnegatively regulates chondrogenic differentiation and terminal differentiation in the growth plate. The aim of this study was to test the hypothesis that leptin may suppress the inhibitory effects of PPARγon growth plate chondrocytes. Chondrocytes were collected from distal femoral growth plates of newborn rats and were cultured in monolayer or cell pellets in the presence or absence of leptin and the PPARγagonist ciglitazone. The results show that leptin attenuates the suppressive effects of PPARγon chondrogenic differentiation and T3-mediated chondrocyte hypertrophy. Leptin treatment also leads to a mild downregulation of PPAR mRNA expression and a significant MAPK/ERK-dependent PPARγphosphorylation at serine 112/82. Blocking MAPK/ERK function with PD98059 confirmed that leptin antagonizes PPARγfunction in growth plate chondrocytes through the MAPK/ERK signaling pathway. Furthermore, leptin signaling in growth plate cells is also negatively modulated by activation of PPARγ, implying that these two signaling pathways are mutually regulated in growth plate chondrocytes.

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microRNA-27a-3p but Not -5p Is a Crucial Mediator of Human Adipogenesis

Cells ◽

10.3390/cells10113205 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3205

Author(s):

Hang Wu ◽

Taner Pula ◽

Daniel Tews ◽

Ez-Zoubir Amri ◽

Klaus-Michael Debatin ◽

...

Keyword(s):

Posttranscriptional Regulation ◽

Adipogenic Differentiation ◽

Regulation Of Gene Expression ◽

Inhibitory Effect ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Inflammatory Conditions ◽

Gene Assay ◽

Sgbs Cells

MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, and inflammatory functions. We previously identified miR-27a being upregulated under inflammatory conditions in human adipocytes and aimed to elucidate its function in adipocyte biology. Both strands of miR-27a, miR-27a-3p and -5p, were downregulated during the adipogenic differentiation of Simpson–Golabi–Behmel syndrome (SGBS) cells, human multipotent adipose-derived stem cells (hMADS), and human primary adipose-derived stromal cells (hASCs). Using miRNA-mimic transfection, we observed that miR-27a-3p is a crucial regulator of adipogenesis, while miR-27a-5p did not alter the differentiation capacity in SGBS cells. In silico screening predicted lipoprotein lipase (LPL) and peroxisome proliferator activated receptor γ (PPARγ) as potential targets of miR-27a-3p. The downregulation of both genes was verified in vitro, and the interaction of miR-27-3p with target sites in the 3′ UTRs of both genes was confirmed via a miRNA-reporter-gene assay. Here, the knockdown of LPL did not interfere with adipogenic differentiation, while PPARγ knockdown decreased adipogenesis significantly, suggesting that miR-27-3p exerts its inhibitory effect on adipogenesis by repressing PPARγ. Taken together, we identified and validated a crucial role for miR-27a-3p in human adipogenesis played by targeting the essential adipogenic transcription factor PPARγ. Though we confirmed LPL as an additional target of miR-27a-3p, it does not appear to be involved in regulating human adipogenesis. Thereby, our findings call the conclusions drawn from previous studies, which identified LPL as a crucial regulator for murine and human adipogenesis, into question.

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