Adipose peroxisome proliferator-activated receptor γ mRNA expression in insulin-resistant obese patients: Relationship with adipocyte membrane phospholipids

The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARγ (peroxisome-proliferator-activated receptor γ) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARγ ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition.

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Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽

10.1155/2020/3817573 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20

Author(s):

Sakil Kulkarni ◽

Jiansheng Huang ◽

Eric Tycksen ◽

Paul F. Cliften ◽

David A. Rudnick

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Transcriptional Regulation ◽

Mitochondrial Gene ◽

Peroxisome Proliferator ◽

Large Set ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Hepatic Expression ◽

Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

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Impact of α-lipoic acid on liver peroxisome proliferator-activated receptor-α, vascular remodeling, and oxidative stress in insulin-resistant rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y11-072 ◽

2011 ◽

Vol 89 (10) ◽

pp. 743-751 ◽

Cited By ~ 11

Author(s):

Adil El Midaoui ◽

Calin Lungu ◽

Hui Wang ◽

Lingyun Wu ◽

Caroline Robillard ◽

...

Keyword(s):

Insulin Resistance ◽

Lipoic Acid ◽

Tap Water ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Cross Sectional ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Resistant ◽

Plasma Ffa ◽

The Impact

This study sought to determine the impact of α-lipoic acid (LA) on superoxide anion (O2•–) production and peroxisome proliferator-activated receptor-α (PPARα) expression in liver tissue, plasma free fatty acids (FFA), and aortic remodeling in a rat model of insulin resistance. Sprague–Dawley rats (50–75 g) were given either tap water or a drinking solution containing 10% D-glucose for 14 weeks, combined with a diet with or without LA supplement. O2•– production was measured by lucigenin chemiluminescence, and PPAR-α expression by Western blotting. Cross-sectional area (CSA) of the aortic media and lumen and number of smooth muscle cells (SMC) were determined histologically. Glucose increased systolic blood pressure (SBP), plasma levels of glucose and insulin, and insulin resistance (HOMA index). All of these effects were attenuated by LA. Whereas glucose had no effect on liver PPAR-α protein level, it decreased plasma FFA. LA decreased the aortic and liver O2•– production, body weight, and plasma FFA levels in control and glucose-treated rats. Liver PPAR-α protein levels were increased by LA, and negatively correlated with plasma FFA. Medial CSA was reduced in all glucose-treated rats, and positively correlated with plasma FFA but not with SBP or aortic O2•– production. Glucose also reduced aortic lumen area, so that the media-to-lumen ratio remained unchanged. The ability of LA to lower plasma FFA appears to be mediated, in part, by increased hepatic PPAR-α expression, which may positively affect insulin resistance. Glucose-fed rats may serve as a unique model of aortic atrophic remodeling in hypertension and early metabolic syndrome.

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Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

Diabetologia ◽

10.1007/s00125-010-1773-1 ◽

2010 ◽

Vol 53 (9) ◽

pp. 2008-2019 ◽

Cited By ~ 82

Author(s):

C. R. Benton ◽

G. P. Holloway ◽

X.-X. Han ◽

Y. Yoshida ◽

L. A. Snook ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Transport ◽

Insulin Signalling ◽

Zucker Rats ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Resistant ◽

Obese Zucker Rats

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Chronic rosiglitazone treatment restores AMPKα2 activity in insulin-resistant rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00096.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. E251-E257 ◽

Cited By ~ 40

Author(s):

Sarah J. Lessard ◽

Zhi-Ping Chen ◽

Matthew J. Watt ◽

Michael Hashem ◽

Julianne J. Reid ◽

...

Keyword(s):

Skeletal Muscle ◽

Zucker Rats ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ampk Signaling ◽

Palmitate Oxidation ◽

Insulin Resistant ◽

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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Apple Flavonols Mitigate Adipocyte Inflammation and Promote Angiogenic Factors in LPS- and Cobalt Chloride-Stimulated Adipocytes, in Part by a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism

Nutrients ◽

10.3390/nu12051386 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1386 ◽

Cited By ~ 1

Author(s):

Danyelle M. Liddle ◽

Meaghan E. Kavanagh ◽

Amanda J. Wright ◽

Lindsay E. Robinson

Keyword(s):

Mrna Expression ◽

Cobalt Chloride ◽

Nuclear Factor Κb ◽

Diglycidyl Ether ◽

Low Grade ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Anti Inflammatory

Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

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Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes

Journal of Applied Physiology ◽

10.1152/japplphysiol.01115.2005 ◽

2006 ◽

Vol 100 (2) ◽

pp. 642-648 ◽

Cited By ~ 40

Author(s):

Xing-Hai Yao ◽

Li Chen ◽

B. L. Grégoire Nyomba

Keyword(s):

Insulin Response ◽

Insulin Injection ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Adult Rats ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Resistant ◽

Adult Rat ◽

Rat Offspring ◽

Before And After

Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA; and phospho enolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50–70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA levels were 40–80% higher in EtOH rats than in controls. Similarly, basal phospho enolpyruvate carboxykinase activity, protein, and mRNA were ∼1.8-fold greater in EtOH rats than in controls. These parameters decreased by ∼50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.

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Opposing Effects of Omega-3 and Omega-6 Long Chain Polyunsaturated Fatty Acids on the Expression of Lipogenic Genes in Omental and Retroperitoneal Adipose Depots in the Rat

Journal of Nutrition and Metabolism ◽

10.1155/2010/927836 ◽

2010 ◽

Vol 2010 ◽

pp. 1-9 ◽

Cited By ~ 35

Author(s):

B. S. Muhlhausler ◽

R. Cook-Johnson ◽

M. James ◽

D. Miljkovic ◽

E. Duthoit ◽

...

Keyword(s):

Mrna Expression ◽

Fatty Acid Synthase ◽

Peroxisome Proliferator ◽

Omega 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Total N ◽

Altered Expression ◽

Lipogenic Genes ◽

Omega 6 ◽

Glycerol 3 Phosphate Dehydrogenase

This study aimed to determine the effect of varying dietary intake of the major n-3 PUFA in human diets,α-linolenic acid (ALA; 18 : 3n-3), on expression of lipogenic genes in adipose tissue. Rats were fed diets containing from 0.095%en to 6.3%en ALA and a constant n-6 PUFA level for 3 weeks. Samples from distinct adipose depots (omental and retroperitoneal) were collected and mRNA expression of the pro-lipogenic transcription factors Sterol-Retinoid-Element-Binding-Protein1c (SREBP1c) and Peroxisome Proliferator Activated Receptor-γ(PPARγ), lipogenic enzymes Sterol-coenzyme Desaturase1 (SCD-1), Fatty Acid Synthase (FAS), lipoprotein lipase (LPL) and glycerol-3-phosphate dehydrogenase (G3PDH) and adipokines leptin and adiponectin determined by qRT-PCR. Increasing dietary ALA content resulted in altered expression of SREBP1c, FAS and G3PDH mRNA in both adipose depots. SREBP1c mRNA expression was related directly to n-6 PUFA concentrations (omental,r2=.71;P<.001; Retroperitoneal,r2=.20;P<.002), and inversely to n-3 PUFA concentrations (omental,r2=.59;P<.001; Retroperitoneal,r2=.19;P<.005) independent of diet. The relationship between total n-6 PUFA and SREBP1c mRNA expression persisted when the effects of n-3 PUFA were controlled for. Altering red blood cell concentrations of n-3 PUFA is thus associated with altered expression of lipogenic genes in a depot-specific manner and this effect is modulated by prevailing n-6 PUFA concentrations.

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