Many mammalian genes are clustered on the genomes, and hence the genes in the same cluster can be regulated through a common regulatory element.  We indeed showed previously that the perilipin/PEX11<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> gene pair is transactivated tissue-selectively by PPAR<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> and PPAR<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>, respectively, through a common binding site.  In the present study, we identified a gene, named GSPA, neighboring a canonical PPAR target, acyl-CoA oxidase (AOX) gene.  GSPA expression was induced by a peroxisome proliferator, Wy14,643, in the liver of wild-type mice, but not PPAR<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>-null mice.  GSPA and AOX share the promoter and two peroxisome proliferator-response elements.  GSPA mRNA was also found in the heart and skeletal muscle, as well as 3T3-L1 cells.  GSPA encodes a protein of 161 amino acids that is enriched in 3T3-L1 cells.   Even other gene pairs might be regulated through common sequence elements, and conversely it would be interesting how each gene is aptly regulated in clusters.

Mst. Hasina Akter

Md. Abdur Razzaque

Liu Yang

Toshio Fumoto

Kiyoto Motojima

Tomohiro Yamaguchi

Fumiko Hirose

Takashi Osumi

Identification of a Gene Sharing a Promoter and Peroxisome Proliferator-Response Elements With Acyl-CoA Oxidase Gene

Polycystic ovary syndrome (PCOS) is the most frequent cause of female infertility. The treatment of PCOS patients with insulin sensitizers, such as metformin or thiazolidinediones, increases the ovulation rate and the number of successful pregnancies. The positive action of the insulin-sensitizing treatments could be explained by a decrease in the peripheral insulin resistance but also by a direct action at the ovarian level. We report in this review different hypotheses of thiazolidinediones actions to improve PCOS (steroid secretion by ovarian cells ; insulin sensitivity in muscle and adipocyte and fat redistribution).

Pascal  Froment

Philippe  Touraine

Thiazolidinediones and Fertility in Polycystic Ovary Syndrome (PCOS)

Osteoporosis is a complex metabolic bone disorder. Recently it has been
appreciated that the “obesity in bone” phenomenon occurs at the expense of bone formation, and that is a key component of the pathology of this disease. Mouse models
with altered bone expression levels of peroxisome proliferator-activated receptor gamma
(PPARG) impact bone formation, but genetic studies connecting <i>PPARG</i> polymorphisms to skeletal phenotypes in humans have proven to be less than satisfactory. One missense polymorphism in exon one has been linked to low bone mineral density (BMD), but the most studied polymorphism, Pro12Ala, has not yet been examined in the context of skeletal phenotype. The studies to date are a promising start in leading to our understanding of the genetic contribution of <i>PPARG</i>  to the phenotypes of BMD and fracture risk.

Cheryl Ackert-Bicknell

Clifford Rosen

The Genetics of <i>PPARG</i> and the Skeleton

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-<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>) acts as a critical positive
regulator of marrow adipocyte formation and as a negative regulator of osteoblast
development. <i>In vivo</i>, increased PPAR-<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> activity leads to bone loss, similar to the bone loss
observed with aging, whereas decreased PPAR-<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> activity results in increased bone mass.
Emerging evidence suggests that the pro-adipocytic and the anti-osteoblastic properties of
PPAR-<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> are ligand-selective, suggesting the existence of multiple mechanisms by which
PPAR-<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> controls bone mass and fat mass in bone.

Beata Lecka-Czernik

Larry J. Suva

Resolving the Two “Bony” Faces of PPAR-

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Evidence from rodent and in vitro models suggests that activation of PPAR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> by thiazolidinediones (TZDs) causes increased bone marrow adiposity anddecreased osteoblastogenesis, resulting in bone loss. TZDs are prescribed forthe treatment of diabetes, providing an opportunity to determine whether PPAR-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> activation also impacts bone in humans. In addition, since type 2 diabetes isassociated with higher fracture risk, an understanding of the clinical impact ofTZDs on bone is needed to guide fracture prevention efforts in this population.This review summarizes current findings regarding type 2 diabetes and increasedfracture risk and then considers the available evidence regarding TZD use andbone metabolism in humans.

Ann V. Schwartz

Diabetes, TZDs, and Bone: A Review of the Clinical Evidence

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-<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> (PPAR<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>), 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 PPAR<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> adenovirus or treated with the PPAR<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> agonist 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 PPAR<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>-infected cells, as was the expression of the chondrogenic 
    genes Col2a1 and aggrecan. Growth plate cells transfected with a PPAR<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> expression plasmid under the control of the collagen <mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>1(II) promoter also demonstrated a similar adipogenic changes. 
    Terminal differentiation of growth plate chondrocytes induced by thyroid hormone was also inhibited by overexpression of PPAR<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> and ciglitazone treatment, with decreased expression 
    of alkaline phosphatase and Runx2/Cbfa1 genes. These in vitro data suggest that PPAR<mml:math id="E10" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> is able to promote adipogenic differentiation in growth plate chondrocytes, while negatively regulating chondrogenic differentiation and terminal differentiation.

Lai Wang

Yvonne Y. Shao

R. Tracy Ballock

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


PPARs and Bone Metabolism

Bone loss occuring with unloading is associated with decreased
osteoblastogenesis and increased bone marrow adipogenesis, resulting in bone loss and decreased bone formation. Here, we review the present knowledge on the role of
PPAR<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> in the control of osteoblastogenesis and bone mass in skeletal unloading. We
showed that PPAR<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> positively promotes adipogenesis and negatively regulates
osteoblast differentiation of bone marrow stromal cells in unloading, resulting in bone
loss. Manipulation of PPAR<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>2 expression by exogenous TGF-<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>2 inhibits the
exaggerated adipogenesis and corrects the balance between osteoblastogenesis
and adipogenesis induced by unloading, leading to prevention of bone loss. This
shows that PPAR<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> plays an important role in the control of bone mass in unloaded
bone. Moreover, this opens the possibility that manipulation of PPAR<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> may correct
the balance between osteoblastogenesis and adipogenesis and prevent bone loss,
which may have potential implications in the treatment of bone loss in clinical
conditions.

P. J. Marie

K. Kaabeche

PPAR Gamma Activity and Control of Bone Mass in Skeletal Unloading

PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> plays a central role in the formation of fat.Regulation of PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> activity depends on numerous factorsranging from dietary ligands to nuclear hormone coactivators andcorepressors to oxygen-sensing mechanisms. In addition, theinterplay of PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> with other nuclear hormone receptorshas implications for the balance between adipogenesis andosteogenesis in mesenchymal stem cells of the bone marrow stroma.This review will explore a range of factors influencingPPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math> activity and how these interactions may affectosteogenesis.

Z. Elizabeth Floyd

Sanjin  Zvonic

Mark E. Nuttall

Jeffrey M. Gimble

Fine-Tuning Reception in the Bone: PPAR<svg style="vertical-align:-3.56265pt" height="12.175" version="1.1" viewBox="0 0 8.6374998 12.175" width="8.6374998" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FE" d="M478 372q0 -39 -31 -97t-61 -98t-78 -98q-45 -55 -73 -102q-13 -79 -13 -197q-11 -11 -43.5 -25.5t-53.5 -15.5l-15 17q5 35 26 101.5t47 123.5q8 72 -1.5 174.5t-37.5 178.5q-14 37 -29 37q-20 0 -67 -65l-25 21q37 60 73 90.5t63 30.5q47 0 72 -112q13 -56 17.5 -141.5&#xA;t0.5 -143.5h2q155 193 155 297q0 26 -12 47q-5 8 -5 15q0 16 12.5 27t29.5 11q21 0 34 -21t13 -55z" /></g></svg> and Company

It has been proposed that PPAR-dependent, accelerated catabolism
of proinflammatory mediators may contribute to the fast resolution
of inflammation. Because retinoid X receptors are obligate
heterodimer partners of PPARs, we investigated the impact of
deleting hepatocyte-specific RXR<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> on the antiedema effect
of PPAR agonists. In wild-type mice (WT), pretreatment
with the PPAR<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>
 agonist perfluorooctanoic acid diminished
carrageenan-induced paw edema by  <mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>66</mml:mn><mml:mo>±</mml:mo><mml:mn>10</mml:mn><mml:mi>%</mml:mi></mml:math>. This effect was
essentially absent (<mml:math id="E4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>13</mml:mn><mml:mo>±</mml:mo><mml:mn>8</mml:mn><mml:mi>%</mml:mi></mml:math>) in hepatocyte-specific
RXR<mml:math id="E5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>-deficient mice. Similarly, pretreatment of
WT mice with the PPAR<mml:math id="E6" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>δ</mml:mi></mml:math>
 agonist L-783483 or the
PPAR<mml:math id="E7" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>
 agonist L-805645 caused <mml:math id="E8" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>54</mml:mn><mml:mo>±</mml:mo><mml:mn>1</mml:mn><mml:mi>%</mml:mi></mml:math> and
<mml:math id="E9" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mn>38</mml:mn><mml:mo>±</mml:mo><mml:mn>8</mml:mn><mml:mi>%</mml:mi></mml:math>
 reduction in carrageenan-induced paw edema,
respectively. These effects were also significantly diminished or
absent in hepatocyte-specific RXR<mml:math id="E10" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>-deficient mice. In
contrast, aspirin reduced carrageenan-induced paw edema equally in
WT and hepatocyte-specific RXR<mml:math id="E11" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math>-deficient mice.
The identification of RXR<mml:math id="E12" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi></mml:math> as an important factor involved
in the antiedema effect produced by agonists of the three PPAR
subtypes is a significant achievement towards the goal of
designing novel, effective anti-inflammatory drugs.

Yu-Jui Yvonne Wan

Mostafa Z. Badr

Inhibition of Carrageenan-Induced Cutaneous Inflammation by PPAR
Agonists Is Dependent on Hepatocyte-Specific Retinoid X Receptor
<i>Alpha</i>

The ligand-dependent recruitment of coactivators to peroxisomeproliferator-activated receptor-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>  (PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>) wasexamined. PPAR-binding protein (PBP), PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B3;</mml:mi></mml:math>coactivator-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> (PGC-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>), steroid receptorcoactivator-1 (SRC-1), and CBP/p300-interacting transactivatorwith ED-rich tail 2 (CITED2) affected PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> activity in thepresence of Wy-14,643. The effects on PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> activity inlight of increased or decreased expression of these coactivatorswere qualitatively different depending on the ligand examined.Diminished expression of PGC-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>, SRC-1, or PBP by RNAiplasmids affected natural or synthetic agonist activity whereasonly Wy-14,643 was affected by decreased PGC-1<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math>. Theinteraction of PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> with an LXXLL-containing peptidelibrary showed ligand-specific patterns, indicative of differencesin conformational change. The association of coactivators toPPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> occurs predominantly via the carboxyl-terminus andmutating <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msup><mml:mi></mml:mi><mml:mrow><mml:mn>456</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math>LHPLL to <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msup><mml:mi></mml:mi><mml:mrow><mml:mn>456</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:math>LHPAA resulted in adominant-negative construct. This research confirms thatcoactivator recruitment to PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>&#x03B1;</mml:mi></mml:math> is ligand-dependent andthat selective receptor modulators (SRMs) of this importantprotein are likely.

Eric S. Tien

Daniel B. Hannon

Jerry T. Thompson

John P. Vanden Heuvel

Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-<svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g></svg> (PPAR<svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><use xlink:href="#x1D6FC"/></g></svg>)

Mostafa Badr

A Forum for a Highly Important and Ever-Expanding Field of Study

About this journal

<p><em>PPAR Research</em> publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.</p>


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<p>Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.</p>


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title

PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

PPAR Research