scholarly journals Resolving the Two “Bony” Faces of PPAR-γ

PPAR Research ◽  
2006 ◽  
Vol 2006 ◽  
pp. 1-9 ◽  
Author(s):  
Beata Lecka-Czernik ◽  
Larry J. Suva
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Fat Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Signals ◽  
Ppar Γ ◽  
Osteoblast Development

Bone loss with aging results from attenuated and unbalanced bone turnover that has been associated with a decreased number of bone forming osteoblasts, an increased number of bone resorbing osteoclasts, and an increased number of adipocytes (fat cells) in the bone marrow. Osteoblasts and adipocytes are derived from marrow mesenchymal stroma/stem cells (MSC). The milieu of intracellular and extracellular signals that controls MSC lineage allocation is diverse. The adipocyte-specific transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) acts as a critical positive regulator of marrow adipocyte formation and as a negative regulator of osteoblast development.In vivo, increased PPAR-γactivity leads to bone loss, similar to the bone loss observed with aging, whereas decreased PPAR-γactivity results in increased bone mass. Emerging evidence suggests that the pro-adipocytic and the anti-osteoblastic properties of PPAR-γare ligand-selective, suggesting the existence of multiple mechanisms by which PPAR-γcontrols bone mass and fat mass in bone.

scholarly journals Growth hormone controls lipolysis by regulation of FSP27 expression

2018 ◽  
Vol 239 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Rita Sharma ◽  
Quyen Luong ◽  
Vishva M Sharma ◽  
Mitchell Harberson ◽  
Brian Harper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Specific Protein ◽  
Negative Regulator ◽  
Gamma Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

scholarly journals Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Yan ◽  
Si-Chi Xu ◽  
Chun-Yan Kong ◽  
Xiao-Yang Zhou ◽  
Zhou-Yan Bian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Injury ◽  
Inflammatory Factors ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Myocardial Oxidative Stress

Background. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice. Methods. To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection. Results. Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-γ (PPAR-γ), and the protective effects of piperine were abolished by the treatment of the PPAR-γ antagonist in vivo and in vitro. Conclusions. Piperine could suppress DOX-related cardiac injury via activation of PPAR-γ in mice.

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

2013 ◽  
Vol 305 (2) ◽  
pp. F143-F154 ◽  
Author(s):  
Harshini Mudaliar ◽  
Carol Pollock ◽  
Muralikrishna Gangadharan Komala ◽  
Steven Chadban ◽  
Huiling Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Responses ◽  
Proximal Tubules ◽  
Peroxisome Proliferator ◽  
Tlr2 Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice

2013 ◽  
Vol 125 (7) ◽  
pp. 329-340 ◽  
Author(s):  
Kai-Chen Wang ◽  
Ching-Piao Tsai ◽  
Chao-Lin Lee ◽  
Shao-Yuan Chen ◽  
Gu-Jiun Lin ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Lipoic Acid ◽  
Inflammatory Cells ◽  
Treg Cells ◽  
Peroxisome Proliferator ◽  
Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Experimental Autoimmune

ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).

scholarly journals Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4250-4258 ◽  
Author(s):  
Raju C. Reddy ◽  
Venkata R. Narala ◽  
Venkateshwar G. Keshamouni ◽  
Jami E. Milam ◽  
Michael W. Newstead ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Human Pmns ◽  
Inflammatory Regulation

AbstractNeutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-γ in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-γ, which is up-regulated by the sepsis-induced cytokines TNF-α and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-γ ligands troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-γ construct. Inhibition of chemotaxis by PPAR-γ ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-γ was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-γ antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-γ activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.

scholarly journals The PPAR-γ antagonist T007 inhibits RANKL-induced osteoclastogenesis and counteracts OVX-induced bone loss in mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiang Li ◽  
Lei Ning ◽  
Jianjun Ma ◽  
Ziang Xie ◽  
Xiangde Zhao ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
In Vitro Assays ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Bone Damage ◽  
Receptor Activator ◽  
Cellular Components

Abstract Background Osteoclasts are key determinant cellular components implicated in the development and progression of disorders driven by bone damage. Herein, we studied the upshot of T007, an antagonist of peroxisome proliferator-activated receptor-gamma (PPARγ), on osteoclastogenesis using cell and animal models. Results The in vitro assays revealed that T007 hindered the osteoclastogenesis caused by the treatment with the receptor activator of nuclear factor-κB ligand (RANKL) through inhibiting the levels of PPARγ in cells. The PPARγ siRNA partially reproduced the inhibitory action of T007. The opposite findings were produced after PPARγ overexpression. Furthermore, T007 prevented from bone loss in a mouse model of osteoporosis induced by ovariectomy (OVX). These findings implied that T007 is a potential efficient drug for the prophylaxis and cure of osteoclast-related disorders. Conclusions Taken together, our findings demonstrated that T007 impedes osteoclastogenesis and will be useful for the therapy of bone related diseases, essentially osteoporosis.

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