• The Zoological Society Korea : Newsletter
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• v.18 no.2
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• pp.6-11
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• 2001

Peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$)에 대한 본격적인 연구는 고지혈증 치료제인 fibrate류의 약물들이 PPAR$\alpha$ activator로 작용한다는 사실이 밝혀짐으로써 크게 증대되었다. PPAR$\alpha$는 fibrate를 포함한 다양한 종류의 peroxisome proiferator (PP)에 의해 활성화되는데 이들을 쥐에 단기간 투여할 경우 간의 peroxisome수와 지 방산 산화효소의 유전자발현이 증가되고 장기간 투여 할 경우 간암을 발생시키지만, fibrate류의 약물들을 고지혈증 환자에게 투여 할 경우 간암을 발생시키지 않으므로써 PP에 대한 반응성에 있어서 species difference를 나타낸다 PPAR$\alpha$는 핵에 존재하는 orphan receptor로서 PP에 의해 활성화되어 9-cis-retinoic acid receptor(RXR)와 heterodimer를 이룬 후 target gene들의 upstream에 있는 peroxisome proliferator response element (PPRE)에 결합하여 target gene들의 발현을 조절한다. 지금까지 연구된 PPAR$\alpha$의 target gene들은 모두 lipid와 lipoprotein 대사를 조절하는 것으로 알려져 있으며, 이러 한 결과들을 기초로 lipid 대사 및 energy balance와 관련된 질병들 - 동맥경화증, 관상동맥질환, 비만, 제 2형 당뇨병 등에서 PPAR$\alpha$의 역할이 집중적으로 연구되고 있다. PPAR$\alpha$가 활성화되면 lipoprotein lipase와 HDL이 증가되고 apo C-III가 감소됨으로써 동맥경화증에 대한 예방적 기능을 나타내고, 몸무게를 감소시킴으로써 비만을 방지할 수 있으며, 인슐린 감수성을 증가시켜 제 2형 당뇨병의 치료효과를 가지는 것으로 보인다. 그러나 PPAR$\alpha$-null mouse에서는 이러한 효과들이 나타나지 않는 것으로 보아 이들 질병에서 PPAR$\alpha$가 중요한 역할을 하는 것으로 생각된다.

• Nutrition Research and Practice
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• v.7 no.6
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• pp.481-487
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• 2013

High-fat diet up-regulates either insulin resistance or triglycerides, which is assumed to be related to the expression of peroxisome proliferator-activated receptor (PPAR)-${\alpha}$ and PPAR-${\gamma}$. The beneficial effects of vitamin E on insulin resistance are well known; however, it is not clear if vitamin E with a high-fat diet alters the expression of PPAR-${\alpha}$ and PPAR-${\gamma}$. We investigated the effects of d-${\alpha}$-tocopherol supplementation on insulin sensitivity, blood lipid profiles, lipid peroxidation, and the expression of PPAR-${\alpha}$ and PPAR-${\gamma}$ in a high-fat (HF) diet-fed male C57BL/6J model of insulin resistance. The animals were given a regular diet (CON; 10% fat), a HF diet containing 45% fat, or a HF diet plus d-${\alpha}$-tocopherol (HF-E) for a period of 20 weeks. The results showed that the HF diet induced insulin resistance and altered the lipid profile, specifically the triglyceride (TG) and total cholesterol (TC) levels (P < 0.05). In this animal model, supplementation with d-${\alpha}$-tocopherol improved insulin resistance as well as the serum levels of TG and very-low-density lipoprotein-cholesterol (VLDL-C) (P < 0.05). Moreover, the treatment decreased the levels of malondialdehyde (MDA) in the serum and liver while increasing hepatic PPAR-${\alpha}$ expression and decreasing PPAR-${\gamma}$ expression. In conclusion, the oral administration of d-${\alpha}$-tocopherol with a high-fat diet had positive effects on insulin resistance, lipid profiles, and oxidative stress through the expression of PPAR-${\alpha}$ and PPAR-${\gamma}$ in a high-fat diet-fed male mice.

• Molecules and Cells
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• v.40 no.6
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• pp.393-400
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• 2017

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by lack of insulin and high glucose levels. T2DM can cause bone loss and fracture, thus leading to diabetic osteoporosis. Promoting osteogenic differentiation of osteoblasts may effectively treat diabetic osteoporosis. We previously reported that Sirtuin 1 (Sirt1), a $NAD^+$-dependent deacetylase, promotes osteogenic differentiation through downregulation of peroxisome proliferator-activated receptor (PPAR) ${\gamma}$. We also found that miR-132 regulates osteogenic differentiation by downregulating Sirt1 in a $PPAR{\beta}/{\delta}$-dependent manner. The ligand-activated transcription factor, $PPAR{\alpha}$, is another isotype of the peroxisome proliferator-activated receptor family that helps maintain bone homeostasis and promot bone formation. Whether the regulatory role of $PPAR{\alpha}$ in osteogenic differentiation is mediated via Sirt1 remains unclear. In the present study, we aimed to determine this role and the underlying mechanism by using high glucose (HG) and free fatty acids (FFA) to mimic T2DM in MC3T3-E1 cells. The results showed that HG-FFA significantly inhibited expression of $PPAR{\alpha}$, Sirt1 and osteogenic differentiation, but these effects were markedly reversed by $PPAR{\alpha}$ overexpression. Moreover, siSirt1 attenuated the positive effects of $PPAR{\alpha}$ on osteogenic differentiation, suggesting that $PPAR{\alpha}$ promotes osteogenic differentiation in a Sirt1-dependent manner. Luciferase activity assay confirmed interactions between $PPAR{\alpha}$ and Sirt1. These findings indicate that $PPAR{\alpha}$ promotes osteogenic differentiation via the Sirt1-dependent signaling pathway.

• Nutrition Research and Practice
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• v.13 no.4
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• pp.286-294
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• 2019

BACKGROUND/OBJECTIVES: Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of ${\alpha}$-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha ($PPAR{\alpha}$). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by $PPAR{\alpha}$. MATERIALS/METHODS: The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among $PPAR{\alpha}$ homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate ($PPAR{\alpha}$ agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. RESULTS: $PPAR{\alpha}$ ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, $PPAR{\alpha}$ activation increased hepatic Acox, Fads1, Fads2, and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex. CONCLUSIONS: LCPUFA enzyme expression was altered by $PPAR{\alpha}$. Either $PPAR{\alpha}$ deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.

• Biomedical Science Letters
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• v.17 no.1
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• pp.13-20
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• 2011

The peroxisome proliferator-activated receptor ${\alpha}$ ($PPAR{\alpha}$) is a nuclear transcription factor that plays a central role in lipid and lipoprotein metabolism. To investigate whether swim training improves obesity and lipid metabolism through $PPAR{\alpha}$ activation in female sham-operated (Sham) and ovariectomized (OVX) mice, we measured body weight, visceral adipose tissue mass, serum free fatty acid at 6 weeks as well as the expression of hepatic $PPAR{\alpha}$ target genes involved in fatty acid oxidation. Swim-trained mice had decreased body weight, visceral adipose tissue mass and serum free fatty acid levels compared to high fat diet fed control mice in both female Sham and OVX mice. These reductions were more prominent in OVX than in Sham mice. Swim training significantly increased hepatic mRNA levels of $PPAR{\alpha}$ target genes responsible for mitochondrial fatty acid ${\beta}$-oxidation, such as carnitine palmitoyltransgerase-1 (CPT-1), very long chain acyl-CoA dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) in OVX mice. However, swim trained female Sham mice did not increase hepatic mRNA levels of $PPAR{\alpha}$ target genes responsible for mitochondrial fatty acid ${\beta}$-oxidation compared to Sham control mice. These results indicate that swim training differentially regulates body weight and adipose tissue mass between OVX and Sham mice, at least in part due to differences in liver $PPAR{\alpha}$ activation.

• Asian-Australasian Journal of Animal Sciences
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• v.18 no.9
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• pp.1221-1225
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• 2005

The peroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear hormone receptors. Lots of studies in rodents and humans have shown that PPARs were involved in lipid metabolism and adipocyte differentiation. The main objective of this work was to detect the single nucleotide polymorphisms (SNPs) in whole coding regions of peroxisome proliferator-activated receptor alpha (PPAR-$\alpha$) and gamma (PPAR-$\gamma$) genes with approach of single strand conformation polymorphism (SSCP) in the chicken population of Arber Acres broiler, Hyline layer and three Chinese native breeds (Shiqiza, Beijing You, Bai'r). Two SNPs of C1029T and C297T were found in chicken PPAR-$\alpha$ and PPAR-$\gamma$ genes respectively and each SNP found three genotypes in the experimental populations. The results showed that the distribution frequency of 3 genotypes in Arber Acres broiler, Hyline layer and Chinese native breeds had significant differences on the PPAR-$\alpha$ and PPAR-$\gamma$ gene respectively (p<0.01). Furthermore, in the PPAR-$\alpha$ gene, the results of least square estimation for genotypes and body composition traits showed the BB genotype birds had higher abdominal fat weight (AFW) and percentage of abdominal fat (AFP) than AA genotype birds (p<0.05). From these we conjecture the PPAR-$\alpha$ and PPAR-$\gamma$ genes were suffered intensive selection during the long term commercial breeding and the PPAR-$\alpha$ gene may be a major gene or linked to the major genes that impact chicken fat metabolism and the SNPs could be used in molecular assistant selection (MAS) as a genetic marker for the chicken fatness traits.

• Biomedical Science Letters
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• v.17 no.4
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• pp.273-281
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• 2011

Our previous study demonstrated that the Korean traditional medicine Gyeongshingangjeehwan (GGEx) inhibits obesity and insulin resistance in obese type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. We investigated whether GGEx may affect AMP-activated protein kinase ${\alpha}$ ($AMPK{\alpha}$) since $AMPK{\alpha}$ activation is known to stimulate fatty acid oxidation in skeletal muscle of obese rodents. After OLETF rats were treated with GGEx, we studied the effects of GGEx on $AMPK{\alpha}$ and acetyl-CoA carboxylase (ACC) phosphorylation, and the expression of $AMPK{\alpha}$, $PPAR{\alpha}$, and $PPAR{\alpha}$ target genes. The effects of GGEx on mRNA expression of the above genes were also measured in C2C12 skeletal muscle cells. Administration of GGEx to OLETF rats for 8 weeks increased phosphorylation of $AMPK{\alpha}$ and ACC in skeletal muscle. GGEx also elevated skeletal muscle mRNA levels of $AMPK{\alpha}1$ and $AMPK{\alpha}2$ as well as $PPAR{\alpha}$ and its target genes. Consistent with the in vivo data, similar activation of genes was observed in GGEx-treated C2C12 cells. These results suggest that GGEx stimulates skeletal muscle $AMPK{\alpha}$ and $PPAR{\alpha}$ activation, leading to alleviation of obesity and related disorders.

• Biomedical Science Letters
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• v.15 no.3
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• pp.179-185
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• 2009

In our previous report, we showed that $PPAR{\gamma}$ does not influence adipogenesis in females with functioning ovaries, indicating that $PPAR{\gamma}$ activity on adipogenesis is associated with sex-related factors. Among the sex-related factors, estrogen has been recognized as a major factor in inhibiting adiposgenesis in females. Thus, we hypothensized that $17{\beta}$-estradiol (E) inhibits 3T3-L1 cell adipogenesis by preventing $PPAR{\gamma}$ activity. E decreased triglyceirde accumulation in differentiated 3T3-L1 cells compared with control group. E also decreased the expression of $PPAR{\gamma}$ mRNA as well as $PPAR{\gamma}$ dependent adipocyte-specific genes, such as adipocyte fatty acid binding protein and tumor necrosis factor $\alpha$. In addition, E not only decreased luciferase reporter activity by $PPAR{\gamma}$, but also transfection of estrogen receptor $\alpha$ ($ER{\alpha}$) or $ER{\beta}$ led to decreases in $PPAR{\gamma}$ reporter gene activation. Moreover, E-activated ERs significantly decreased the luciferase reporter gene activation induced by $PPAR{\gamma}$ transfection, suggesting that estrogen-activated ERs inhibit $PPAR{\gamma}$-dependent transactivation. Accordingly, our results demonstrate that E inhibits the action of $PPAR{\gamma}$ on adipogenesis through E activated ER, providing evidence that lack of estrogen may potentiate $PPAR{\gamma}$ action on adipogenesis.

• Biomedical Science Letters
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• v.19 no.1
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• pp.17-24
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• 2013

Animals show a sexual dimorphism in metabolic responses. We investigated to verify whether the peroxisome proliferator-activated receptor ${\alpha}$ ($PPAR{\alpha}$) agonist fenofibrate regulates obesity and skeletal muscle lipid metabolism with sexual dimorphism and to determine the changes in skeletal muscle expression of $PPAR{\alpha}$ target genes. After both sexes of C57BL/6J mice received a high fat diet with or without fenofibrate for 7 weeks, we examined the effects of fenofibrate on not only body weight, adipose tissue mass, and skeletal muscle lipid accumulation, but also the mRNA expression of $PPAR{\alpha}$-related genes in skeletal muscle. Male mice given a fenofibrate-supplemented high fat diet showed decreased body weight gain and adipose tissue mass compared with mice fed a high fat diet alone, whereas fenofibrate did not reduce them in high fat diet-fed female mice. Lipid accumulation in skeletal muscle was inhibited by fenofibrate in male mice, but not in female mice. Gene expression analysis revealed that fenofibrate increased the mRNA levels of $PPAR{\alpha}$ target enzymes only in male mice. Therefore, our results suggest that sex-dependence differences in obesity and intramuscular lipid levels under fenofibrate treatment could be due in part to the differences in skeletal muscle $PPAR{\alpha}$ activation between male and female mice.

• Biomedical Science Letters
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• v.16 no.4
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• pp.239-246
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• 2010

It is suggested that ovariectomy induces body weight gain primarily in the form of adipose tissue in rodents. Since liver peroxisome proliferator-activated receptor ${\alpha}$ (PPAR${\alpha}$) and uncoupling 2 (UCP2) are involved in the regulation of energy expenditure, it was investigated whether swim training regulates ovariectomy-induced adiposity and steatosis through liver PPAR${\alpha}$ and UCP2 activation in female ovariectomized mice, an animal model of postmenopausal women. Swim-trained mice had significantly decreased adipose tissue weights compared with sedentary control mice. Histological analysis showed that hepatic lipid accumulation was inhibited by swim training. Concomitantly, swim training significantly increased mRNA levels of PPAR${\alpha}$ and its target genes responsible for peroxisomal fatty acid ${\beta}$-oxidation, such as acyl-CoA oxidase, enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase and thiolase in the liver. Moreover, swim training induced the mRNA expression of UCP2. These results suggest that swim training can effectively prevent adiposity and steatosis caused by ovariectomy, in part through activation of liver PPAR${\alpha}$ and UCP2 in female obese mice.