Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 μM RSG increased ( P < 0.05) AMPKα1 activity and phosphorylation of AMPK (Thr172). In addition, acetyl-CoA carboxylase (Ser218) phosphorylation and palmitate oxidation were increased ( P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 μl/100 g body mass), or 3 mg/kg RSG. AMPKα1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKα2 activity was ∼25% lower in obese vs. lean animals ( P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity ( P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

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PPAR-α activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00937.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. H2187-H2195 ◽

Cited By ~ 35

Author(s):

Xueying Zhao ◽

Jeffrey E. Quigley ◽

Jianghe Yuan ◽

Mong-Heng Wang ◽

Yiqing Zhou ◽

...

Keyword(s):

Zucker Rats ◽

Peroxisome Proliferator ◽

Eicosanoid Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Cholesterol Levels ◽

Renal Vessels ◽

Obese Rats ◽

Obese Zucker Rats ◽

Renal Vascular

Previous studies have shown that the synthesis of renal cytochrome P-450 (CYP)-derived eicosanoids is downregulated in genetic or high-fat diet-induced obese rats. Experiments were designed to determine whether fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, would induce renal eicosanoid synthesis and improve endothelial function in obese Zucker rats. Administration of fenofibrate (150 mg·kg−1·day−1 for 4 wk) significantly reduced plasma insulin, triglyceride, and total cholesterol levels in obese Zucker rats. CYP2C11 and CYP2C23 proteins were downregulated in renal vessels of obese Zucker rats. Consequently, renal vascular epoxygenase activity decreased by 15% in obese Zucker rats compared with lean controls. Chronic fenofibrate treatment significantly increased renal cortical and vascular CYP2C11 and CYP2C23 protein levels in obese Zucker rats, whereas it had no effect on epoxygenase protein and activity in lean Zucker rats. Renal cortical and vascular epoxygenase activities were consequently increased by 54% and 18%, respectively, in fenofibrate-treated obese rats. In addition, acetylcholine (1 μM)-induced vasodilation was significantly reduced in obese Zucker kidneys (37% ± 11%) compared with lean controls (67% ± 9%). Chronic fenofibrate administration increased afferent arteriolar responses to 1 μM of acetylcholine in obese Zucker rats (69% ± 4%). Inhibition of the epoxygenase pathway with 6-(2-propargyloxyphenyl)hexanoic acid attenuated afferent arteriolar diameter responses to acetylcholine to a greater extent in lean compared with obese Zucker rats. These results demonstrate that the PPAR-α agonist fenofibrate increased renal CYP-derived eicosanoids and restored endothelial dilator function in obese Zucker rats.

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Activation of Peroxisome Proliferator-Activated Receptor (PPAR) Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

Diabetes ◽

10.2337/db07-1318 ◽

2007 ◽

Vol 57 (2) ◽

pp. 332-339 ◽

Cited By ~ 231

Author(s):

U. Riserus ◽

D. Sprecher ◽

T. Johnson ◽

E. Olson ◽

S. Hirschberg ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Metabolic Abnormalities ◽

Peroxisome Proliferator Activated Receptor

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The peroxisome proliferator-activated receptor agonist pioglitazone and 5-lipoxygenase inhibitor zileuton have no effect on lung inflammation in healthy volunteers by positron emission tomography in a single-blind placebo-controlled cohort study

PLoS ONE ◽

10.1371/journal.pone.0191783 ◽

2018 ◽

Vol 13 (2) ◽

pp. e0191783 ◽

Cited By ~ 4

Author(s):

Delphine L. Chen ◽

Howard J. Huang ◽

Derek E. Byers ◽

Adrian Shifren ◽

Bryan Belikoff ◽

...

Keyword(s):

Positron Emission Tomography ◽

Cohort Study ◽

Lung Inflammation ◽

Receptor Agonist ◽

Emission Tomography ◽

Peroxisome Proliferator ◽

Lipoxygenase Inhibitor ◽

Peroxisome Proliferator Activated Receptor ◽

Positron Emission ◽

Single Blind

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The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

Hepatology Communications ◽

10.1002/hep4.1057 ◽

2017 ◽

Vol 1 (6) ◽

pp. 524-537 ◽

Cited By ~ 42

Author(s):

Guillaume Wettstein ◽

Jean-Michel Luccarini ◽

Laurence Poekes ◽

Patrick Faye ◽

Francine Kupkowski ◽

...

Keyword(s):

Receptor Agonist ◽

Metabolic Disorders ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

New Generation

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AVE0991, a Nonpeptide Angiotensin 1-7 Receptor Agonist, Improves Glucose Metabolism in the Skeletal Muscle of Obese Zucker Rats: Possible Involvement of Prooxidant/Antioxidant Mechanisms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6372935 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Viktoria Dobrocsyova ◽

Miroslava Slamkova ◽

Katarina Krskova ◽

Lucia Balazova ◽

Maciej Suski ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Tolerance ◽

Insulin Signaling ◽

Receptor Agonist ◽

Colorimetric Assay ◽

Whole Body ◽

Zucker Rats ◽

Ros Generation ◽

Morbidly Obese ◽

Obese Zucker Rats

Angiotensin 1-7 (Ang 1-7) enhances insulin signaling and glucose transport activity in the skeletal muscle. The aim of our study was to evaluate the effect of AVE0991, a nonpeptide Mas receptor agonist, on the metabolic parameters, expression of RAS components and markers of oxidative stress, and insulin signaling in the skeletal morbidly obese rats. 33-week-old male obese Zucker rats were treated with vehicle and AVE0991 (0.5 mg/kg BW/day) via osmotic minipumps for two weeks. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps. The enzymatic activities were detected flourometrically (aminopeptidase A) or by colorimetric assay kit (protein tyrosine phosphatase 1B). Administration of AVE0991 enhanced insulin signaling cascade in the skeletal muscle, reflected by improved whole-body glucose tolerance. It has been shown that reactive oxygen species (ROS) have insulin-mimetic action in muscle. The expression of renin receptor, transcription factor PLZF, and prooxidant genes was upregulated by AVE0991 accompanied by elevated expression of genes coding enzymes with antioxidant action. Our results show that AVE0991 administration activates genes involved in both ROS generation and clearance establishing a new prooxidant/antioxidant balance on a higher level, which might contribute to the improved insulin signaling pathway and glucose tolerance of obese Zucker rats.

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