scholarly journals Systemic Administration of Insulin Receptor Antagonist Results in Endothelial and Perivascular Adipose Tissue Dysfunction in Mice

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1448
Author(s):  
Bartosz Proniewski ◽  
Anna Bar ◽  
Anna Kieronska-Rudek ◽  
Joanna Suraj-Prażmowska ◽  
Elżbieta Buczek ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Function ◽  
Insulin Receptor ◽  
Receptor Antagonist ◽  
Insulin Signaling ◽  
Uncoupling Protein ◽  
Vascular Pathology ◽  
Resonance Spectroscopy ◽  
No Production ◽  
Perivascular Adipose Tissue

Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity.

Abstract P099: Loss Of The Brown-Like Phenotype Of Aortic PVAT Is Associated With Mitochondrial Dysfunction In Obesity-Induced Endothelial Dysfunction In Female Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Nicole Maddie ◽  
Maria Alicia A Carrillo-sepulveda
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mitochondrial Dysfunction ◽  
Uncoupling Protein ◽  
Obese Group ◽  
Female Rats ◽  
Chow Diet ◽  
Anatomical Location ◽  
Perivascular Adipose Tissue

Endothelial dysfunction is a major complication of obesity and is an early contributor to hypertension. Perivascular adipose tissue (PVAT) surrounds most blood vessels and has different phenotypic properties based on its anatomical location. Thoracic aortic PVAT from humans and rodents is a brown-like adipose tissue and plays a vasculo-protective role under physiological conditions. In obesity, aortic PVAT expands, switches from a brown-like to a white-like phenotype and contributes to endothelial dysfunction. We hypothesized that loss of the brown-like phenotype of aortic PVAT in obesity is associated with mitochondrial dysfunction, resulting in PVAT and endothelial dysfunction. Eight-week-old female Wistar rats were randomized into two experimental groups: the Lean group (n=8) received a chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) and the Obese group (n=8) received a western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein), for 20 weeks. Increased body weight (340.57 vs. 265.37g leans, p<0.05) was confirmed in the obese group. At the experimental endpoint, thoracic aortas with intact (+PVAT) or removed PVAT (-PVAT) were obtained for analysis. Endothelial function was assessed in aortic rings +PVAT or -PVAT by performing concentration-response to acetylcholine using wire myography. The aortic ring (-PVAT) from the obese group exhibited impaired endothelium-dependent vasodilation (p<0.01). This effect was heightened in aortic rings (+PVAT) (p<0.05), showing a negative effect of PVAT on endothelial function during obesity. Mitochondrial dysfunction in PVAT from the obese group was characterized by decreased mitochondrial density (30% reduction, p<0.05), detected by quantification of Mitotracker fluorescence, and increased reactive oxygen species levels (4.34-fold increase, p<0.01), as evidenced by DHE staining. These effects were accompanied by decreased uncoupling protein-1 expression in the obese group (55% reduction, p<0.01). Moreover, Oil Red O staining showed larger lipid droplets in aortic PVAT from the obese group. Our results support that obesity-induced endothelial dysfunction is associated with a loss of the brown-like phenotype and mitochondrial dysfunction in PVAT.

scholarly journals Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice

2017 ◽  
Vol 42 (2) ◽  
pp. 603-614 ◽  
Author(s):  
Ningning Hou ◽  
Gang Du ◽  
Fang Han ◽  
Jin Zhang ◽  
Xiaotong Jiao ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Heme Oxygenase ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
No Production ◽  
Obese Mice ◽  
Perivascular Adipose Tissue ◽  
Tnf Α

Aims: To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. Methods: Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT–) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-α gene expression in PVAT were tested by real-time PCR. Results: The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF-α expression in PVAT. Conclusion: Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity.

scholarly journals Insulin Receptor Substrate 2 Controls Insulin-Mediated Vasoreactivity and Perivascular Adipose Tissue Function in Muscle

2018 ◽  
Vol 9 ◽  
Author(s):  
Alexander H. Turaihi ◽  
Wineke Bakker ◽  
Victor W. M. van Hinsbergh ◽  
Erik H. Serné ◽  
Yvo M. Smulders ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Perivascular Adipose Tissue

Changes in dietary sodium consumption modulate GLUT4 gene expression and early steps of insulin signaling

2004 ◽  
Vol 286 (4) ◽  
pp. R779-R785 ◽  
Author(s):  
Maristela Mitiko Okamoto ◽  
Dóris Hissako Sumida ◽  
Carla Roberta Oliveira Carvalho ◽  
Alessandra Martins Vargas ◽  
Joel Cláudio Heimann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Dietary Sodium ◽  
Glut4 Translocation ◽  
Glut4 Gene Expression

Previous studies have shown that chronic salt overload increases insulin sensitivity, while chronic salt restriction decreases it. In the present study we investigated the influence of dietary sodium on 1) GLUT4 gene expression, by Northern and Western blotting analysis; 2) in vivo GLUT4 protein translocation, by measuring the GLUT4 protein in plasma membrane and microsome, before and after insulin injection; and 3) insulin signaling, by analyzing basal and insulin-stimulated tyrosine phosphorylation of insulin receptor (IR)-β, insulin receptor substrate (IRS)-1, and IRS-2. Wistar rats were fed normal-sodium (NS-0.5%), low-sodium (LS-0.06%), or high-sodium diets (HS-3.12%) for 9 wk and were killed under pentobarbital anesthesia. Compared with NS rats, HS rats increased ( P < 0.05) the GLUT4 protein in adipose tissue and skeletal muscle, whereas GLUT4 mRNA was increased only in adipose tissue. GLUT4 expression was unchanged in LS rats compared with NS rats. The GLUT4 translocation in HS rats was higher ( P < 0.05) both in basal and insulin-stimulated conditions. On the other hand, LS rats did not increase the GLUT4 translocation after insulin stimulus. Compared with NS rats, LS rats showed reduced ( P < 0.01) basal and insulin-stimulated tyrosine phosphorylation of IRS-1 in skeletal muscle and IRS-2 in liver, whereas HS rats showed enhanced basal tyrosine phosphorylation of IRS-1 in skeletal muscle ( P < 0.05) and of IRS-2 in liver. In summary, increased insulin sensitivity in HS rats is related to increased GLUT4 gene expression, enhanced insulin signaling, and GLUT4 translocation, whereas decreased insulin sensitivity of LS rats does not involve changes in GLUT4 gene expression but is related to impaired insulin signaling.

scholarly journals The Lou/C rat: a model of spontaneous food restriction associated with improved insulin sensitivity and decreased lipid storage in adipose tissue

2009 ◽  
Vol 296 (5) ◽  
pp. E1120-E1132 ◽  
Author(s):  
Christelle Veyrat-Durebex ◽  
Xavier Montet ◽  
Manlio Vinciguerra ◽  
Asllan Gjinovci ◽  
Paolo Meda ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Food Restriction ◽  
Wistar Rats ◽  
Uncoupling Protein ◽  
Caloric Intake ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

The inbred Lou/C rat, originating from the Wistar strain, has been described as a model of resistance to diet-induced obesity, but little is known about its metabolism. Since this knowledge could provide some clues about the etiology of obesity/insulin resistance, this study aimed at characterizing glucose and lipid metabolism in Lou/C vs. Wistar rats. This was achieved by performing glucose and insulin tolerance tests, euglycemic hyperinsulinemic clamps, and characterization of intracellular insulin signaling in skeletal muscle. Substrate-induced insulin secretion was evaluated using perfused pancreas and isolated islets. Finally, body fat composition and the expression of various factors involved in lipid metabolism were determined. Body weight and caloric intake were lower in Lou/C than in Wistar rats, whereas food efficiency was similar. Improved glucose tolerance of Lou/C rats was not related to increased insulin output but was related to improved insulin sensitivity/responsiveness in the liver and in skeletal muscles. In the latter tissue, this was accompanied by improved insulin signaling, as suggested by higher activation of the insulin receptor and of the Akt/protein kinase B pathway. Fat deposition was markedly lower in Lou/C than in Wistar rats, especially in visceral adipose tissue. In the inguinal adipose depot, expression of uncoupling protein-1 was detected in Lou/C but not in Wistar rats, in keeping with a higher expression of peroxisome proliferator-activated receptor-γ coactivator-1 in these animals. The Lou/C rat is a valuable model of spontaneous food restriction with associated improved insulin sensitivity. Independently from its reduced caloric intake, it also exhibits a preferential channeling of nutrients toward utilization rather than storage.

scholarly journals Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats

2021 ◽  
Vol 22 (24) ◽  
pp. 13671
Author(s):  
Marcelo Queiroz ◽  
Adriana Leandro ◽  
Lara Azul ◽  
Artur Figueirinha ◽  
Raquel Seiça ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Endothelial Function ◽  
Metabolic Parameters ◽  
Perivascular Adipose Tissue ◽  
Gk Rats ◽  
Vascular Oxidative Stress ◽  
Luteolin Treatment

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

scholarly journals Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats

2021 ◽  
Vol 22 (5) ◽  
pp. 2469
Author(s):  
Katarzyna Szkudelska ◽  
Marzanna Deniziak ◽  
Maciej Sassek ◽  
Ignacy Szkudelski ◽  
Wojciech Noskowiak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Binding Capacity ◽  
Receptor Expression ◽  
Biologically Active ◽  
Blood Levels ◽  
Gk Rats

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue.

Abstract P242: Perivascular Adipose Tissue Regulates Endothelial Function And Glucose Disposal Via Leptin Control Of The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 / NADPH Oxidase 1 Pathways

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Reem T Atawia ◽  
Thiago B Bruder-nascimento ◽  
Tetsuo Horimatsu ◽  
Xueyi Li ◽  
Simone Kennard ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Endothelial Function ◽  
Leptin Receptor ◽  
Critical Role ◽  
Underlying Mechanism ◽  
Glucose Disposal ◽  
Perivascular Adipose Tissue ◽  
Nadph Oxidase 1 ◽  
Signaling Activation

Our group has previously reported that lack of adipose tissue (lipodystrophy) leads to glucose intolerance and impaired endothelial-dependent vasorelaxation (EDR) via reduced signaling of the adipokine, leptin in the endothelium. However, the identity of the adipose depot responsible for endothelial leptin signaling activation and the underlying mechanism remains ill-defined. Our new data indicate that the perivascular adipose tissue (PVAT) is an important source of leptin. Thus, we hypothesized that leptin specifically derived from PVAT restores EDR and glucose tolerance in a mouse model with global deficiency in adipose tissue (lipodystrophic, BSCL2 -/- ). Restoration of PVAT in BSCL2 -/- mice corrected systemic glycemic status (GTT AUC, BSCL2 -/- + PVAT 635.3 ± 31.28 vs sham 741.6 ± 45.87, p<0.05). Moreover, PVAT transplantation restored EDR locally (abdominal aorta EDR AUC, BSCL2 -/- + PVAT 224.9 ± 23.97 vs 109 ± 19, P<0.05) but not systemically (thoracic aorta EDR AUC, BSCL2 -/- + PVAT 143.8 ± 22.29 vs sham 131.3 ± 11.54, P<0.05), indicating a distinctive paracrine role for PVAT-derived leptin in the vasculature. Concomitantly, we reported that inhibition of endothelial glycolysis, the main bioenergetic pathway of endothelial cells, via inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a major regulator of the glycolytic pathway, significantly improved endothelial function in both lipodystrophic mice and endothelial leptin receptor (LepR) deficient mice, as leptin does. Also, endothelial cells extracted from aortas of BSCL2 -/- mice showed a trend towards an increase in PFKFB3 mRNA expression compared to WT mice. Moreover, we found that overexpression of PFKFB3 in aortic rings and endothelial cells impaired EDR and increased the ROS generating enzyme, Nox1 expression, respectively. Collectively, our results showed the critical role of PVAT-driven leptin and endothelial leptin receptor signaling in regulating systemic glucose disposal as well as endothelial function via a mechanism that potentially regulates endothelial glycolysis and oxidative stress-mediated via PFKFB3/NOX1.

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