Vascular function in the metabolic syndrome and the effects on skeletal muscle perfusion: lessons from the obese Zucker rat

2006 ◽  
Vol 42 ◽  
pp. 145-160 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
Michael D. Delp
Keyword(s):  
Metabolic Syndrome ◽  
Vascular Function ◽  
Human Condition ◽  
Therapeutic Interventions ◽  
Western Society ◽  
Zucker Rat ◽  
Metabolic Demand ◽  
Muscle Perfusion ◽  
The Metabolic Syndrome ◽  
Obese Zucker Rat

The increased prevalence of obesity in Western society has been well established for many years, and with this trend, the prevalence of other associated pathologies including insulin resistance, dyslipidaemia, hypertension and the genesis of a proinflammatory and prothrombotic environment within individuals is also rapidly increasing, resulting in a condition known as the~metabolic syndrome. From a physiological perspective, one of the most severe consequences of the metabolic syndrome is a progressive inability of the cardiovascular system to adequately perfuse tissues and organs during either elevated metabolic demand and, if sufficiently severe, under basal levels of demand. For the study of the metabolic syndrome, the OZR (obese Zucker rat) represents an important tool in this effort, as the metabolic syndrome in these animals results from a chronic hyperphagia, and thus can be an excellent representation of the human condition. As in afflicted humans, OZR experience an attenuated functional and reactive hyperaemia, and can ultimately experience an ischaemic condition in their skeletal muscles at rest. The source of this progressive ischaemia appears to lie at multiple sites, as endothelium-dependent vasodilator responses are strongly impaired in OZR, and specific constrictor processes (e.g. adrenergic tone) may be enhanced. Whilst these active processes may contribute to a reduction in blood flow under resting conditions or with mild elevations in metabolic demand, an evolving structural alteration to individual microvessels (reduced distensibility) and microvascular networks (reduced microvessel density) also develop and may act to constrain perfusion at higher levels of metabolic demand. Given that constrained muscle perfusion in the metabolic syndrome appears to reflect a highly integrated, multi-faceted effect in OZR, and probably in humans as well, therapeutic interventions must be designed to address each of these contributing elements.

Red raspberry (Rubus idaeus) consumption restores the impaired vasoconstriction and vasorelaxation in the aorta of the obese zucker rat, a model of the metabolic syndrome

2020 ◽  
pp. 1-13
Author(s):  
Natalie E. VandenAkker ◽  
Stefano Vendrame ◽  
Panagiotis Tsakiroglou ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Metabolic Syndrome ◽  
Vascular Function ◽  
Vascular Tone ◽  
Rubus Idaeus ◽  
Relaxation Response ◽  
Zucker Rat ◽  
Red Raspberry ◽  
The Metabolic Syndrome ◽  
Obese Zucker Rat ◽  
Pre Treatment

Metabolic Syndrome (MetS) increases the risk of cardiovascular disease. Whole red raspberry (WRR) consumption on vascular function was investigated in the obese Zucker rat (OZR), model of MetS. Male OZR and their lean littermates (LZR) were placed on a control (C) or an 8% w/w WRR-enriched diet for 8 weeks. Phenylephrine (Phe)-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation were measured in aortic rings in the presence or absence of L-N-monomethyl-arginine (L-NMMA) and mefenamic acid (MFA). Phe-induced vasoconstriction was lower in the OZR-C compared to LZR-C (p <  0.05). The WRR diet partially restored aortic response in the OZR-WRR aorta (p <  0.05) compared to OZR- C. The OZR-WRR group pre-treated with L-NMMA increased compared to OZR-C (p <  0.05). Pre-treatment with L-NMMA, maximal relaxation response was higher in the OZR compared to the LZR (p <  0.05). With L-NMMA, maximal relaxation response in OZR-WRR (p <  0.05) was lower compared to the OZR-C. Prostacyclin I2 concentration was higher in the OZR compared to the LZR (p <  0.05) and was attenuated in the OZR-WRR (p <  0.05). Aortic expression of eNOS and COX-2 were downregulated in the OZR-WRR (p <  0.05). In conclusion, WRR restores the impaired vascular tone of the OZR by enhancing Phe-induced vasoconstriction and attenuating Ach-induced vasorelaxation.

scholarly journals Red raspberry (Rubus idaeus) consumption attenuates inflammation in the obese Zucker rat, a model of the Metabolic Syndrome (OR24-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Natalie VandenAkker ◽  
Stefano Vendrame ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Metabolic Syndrome ◽  
Body Weight ◽  
Food Consumption ◽  
Zucker Rat ◽  
Red Raspberry ◽  
High Blood Glucose ◽  
The Metabolic Syndrome ◽  
Obese Zucker Rat ◽  
Tnf Α ◽  
Inflammatory State

Abstract Objectives Metabolic syndrome (MetS) is a major public health problem that is escalating quickly globally. MetS is defined as a combination of obesity, high blood pressure, high blood glucose, low high-density lipoprotein and high cholesterol resulting in a pro-thrombotic and pro-inflammatory state. This study investigated the effect of whole red raspberry (WRR) consumption on inflammation in the obese Zucker rat (OZR), a model of the MetS. Methods At 8 weeks of age, male OZR (n = 16) and their lean littermates (LZR) (n = 16) were placed on a control (C) or an 8% w/w WRR-enriched diet for 8 weeks. Body weight and daily food consumption was measured. Circulating levels of inflammatory cytokines and their gene expression in the liver and adipose tissue (AT) were evaluated. Results No significant differences were observed in body weight or food consumption between diet groups. Consumption of WRR significantly reduced the plasma level of pro-inflammatory molecule, C-reactive protein (CRP) in the OZR compared to OZR-C (1024 ± 108.74 μg/ml vs 4250 ± 1120.12 μg/ml, p < 0.05) respectively. Plasma levels of interleukin-6 (IL-6), a pro-inflammatory cytokine decreased in the OZR consuming a WRR diet compared to the OZR-C (20.69 ± 1.41 pg/ml vs 50.50 ± 3.66 pg/ml, p < 0.0001) respectively. Following the consumption of WRR, the expression of pro-inflammatory molecules IL-6 and tumor necrosis factor-alpha (TNF-α) in the OZR significantly down-regulated (p < 0.01 and p < 0.05) respectively, in the AT. The expression of pro-inflammatory markers IL-6, TNF-α, and nuclear factor kappa-B (NF-ΚB) also significantly down-regulated (p < 0.01, p < 0.0001 and p < 0.05) respectively, following the consumption of WRR in the OZR compared to the OZR-C. Conclusions The results from the present study demonstrate that daily consumption of WRR improves the pro-inflammatory state associated with MetS. Funding Sources National Processed Raspberry Council USDA National Institute of Food and Agriculture Hatch FutureCeuticals (Momence, IL USA)

Whole Red Raspberry (Rubus idaeus)-Enriched Diet Is Hepatoprotective in the Obese Zucker Rat, a Model of the Metabolic Syndrome

2020 ◽  
Author(s):  
Natalie E. VandenAkker ◽  
Stefano Vendrame ◽  
Panagiotis Tsakiroglou ◽  
Marissa McGilvrey ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Metabolic Syndrome ◽  
Rubus Idaeus ◽  
Zucker Rat ◽  
Red Raspberry ◽  
The Metabolic Syndrome ◽  
Obese Zucker Rat

Habitual Physical Exercise Improves Macrophage IL-6 and TNF-α Deregulated Release in the Obese Zucker Rat Model of the Metabolic Syndrome

2011 ◽  
Vol 18 (2) ◽  
pp. 123-130 ◽  
Author(s):  
Leticia Martín-Cordero ◽  
Juan José García ◽  
María Dolores Hinchado ◽  
Elena Bote ◽  
Rafael Manso ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Physical Exercise ◽  
Rat Model ◽  
Zucker Rat ◽  
The Metabolic Syndrome ◽  
Obese Zucker Rat ◽  
Tnf Α

Abstract 3203: The role of Neprilysin in the Development of Insulin Resistance, Type 2 Diabetes and Cardiovascular Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kristina F Standeven ◽  
Angela M Carter ◽  
Anthony J Balmforth ◽  
Stephen B Wheatcroft ◽  
Nigel M Hooper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Vascular Function ◽  
Animal Studies ◽  
Obese Mice ◽  
Human Adipocytes ◽  
The Metabolic Syndrome ◽  
Mesenteric Fat ◽  
Order Of Magnitude ◽  
Average Gene

Neprilysin (NEP) cleaves several bioactive peptides involved in the regulation of vascular function. In human microvascular endothelial cells, fatty acids and glucose increase NEP activity, and inhibition of NEP in animal studies results in increased insulin sensitivity, suggesting that NEP may be related to the metabolic syndrome. We tested this hypothesis in cell, animal and human based models. Microarray analysis of mRNA expression in differentiated human adipocytes (Affymetrix Human Genome U133 Plus 2.0 arrays) showed NEP expression to be an order of magnitude higher than the average gene signal, suggesting that human adipocytes express high endogenous levels of NEP mRNA. Real time PCR confirmed high levels of NEP mRNA in preadipocytes which increased 28 fold during differentiation and reached levels equivalent to the endogenous control, GAPDH, by 14 days. We created a diet induced model of obesity by feeding male C57BL/6J mice a high-fat diet, which resulted in decreased glucose tolerance and insulin resistance in obese mice. Plasma NEP levels measured after 15 weeks of feeding were significantly higher in obese mice (1642 [± 529]) pg/μl) compared to lean mice (820 [± 487] pg/μl) (p < 0.01). NEP levels increased 4- and 9-fold in epididymal and mesenteric fat in obese, compared to lean, mice. In a study of 318 healthy white European males, plasma NEP measured by activity assay was significantly higher in subjects with the metabolic syndrome (MetS) and levels increased progressively with increasing number of MetS components, being ~8-fold higher in those with 5 MetS components compared with those with none. NEP correlated with insulin, HOMA and BMI in all subjects. In conclusion, we have generated cell, murine and human data which suggest that NEP may have an important role in cardio-metabolic risk associated with insulin resistance, with the adipocyte as a major source of NEP. These findings indicate that NEP is a novel adipokine that links insulin resistance to vascular risk.

scholarly journals Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome

2009 ◽  
Vol 296 (6) ◽  
pp. R1771-R1782 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
John M. Hollander ◽  
Robert W. Brock ◽  
Han-Gang Yu ◽  
Matthew A. Boegehold
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Vascular Reactivity ◽  
Oxidant Stress ◽  
Zucker Rats ◽  
Minimal Effect ◽  
Metabolic Demand ◽  
The Metabolic Syndrome ◽  
The Impact

Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs. lean Zucker rats (LZR), although dilation to adenosine was intact. Increased adrenergic tone (phenylephrine) or intralumenal pressure (ILP) impaired dilation in both strains (OZR>LZR). Treatment of OZR arterioles with Tempol (superoxide dismutase mimetic) or SQ-29548 (prostaglandin H2/thromboxane A2 receptor antagonist) improved dilator reactivity under control conditions and with increased ILP, but had minimal effect with increased adrenergic tone. Arteriolar dilation to adenosine was well maintained in both strains under all conditions. For in situ cremasteric arterioles, muscle contraction-induced elevations in metabolic demand elicited arteriolar dilations and hyperemic responses that were blunted in OZR vs. LZR, although distal parallel arterioles were characterized by heterogeneous dilator and perfusion responses. α-Adrenoreceptor blockade improved outcomes at rest but had minimal effect with elevated metabolic demand. Treatment with Tempol or SQ-29548 had minimal impact at rest, but lessened distal arteriolar perfusion heterogeneity with increased metabolic demand. In blood-perfused gastrocnemius of OZR, perfusion was constrained primarily by adrenergic tone, while myogenic activation and endothelium-dependent dilation did not appear to contribute significantly to ischemia. These results of this novel, integrated approach suggest that adrenergic tone and metabolic dilation are robust determinants of bulk perfusion to skeletal muscle of OZR, while endothelial dysfunction may more strongly regulate perfusion distribution homogeneity via the impact of oxidant stress and AA metabolism.

Impaired hemorrhage tolerance in the obese Zucker rat model of metabolic syndrome

2006 ◽  
Vol 100 (2) ◽  
pp. 465-473 ◽  
Author(s):  
Jefferson C. Frisbee
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Arterial Pressure ◽  
Blood Volume ◽  
Zucker Rats ◽  
Total Blood Volume ◽  
Total Blood ◽  
Muscle Perfusion ◽  
The Metabolic Syndrome ◽  
Arteriolar Tone

As obese Zucker rats (OZR) manifesting the metabolic syndrome exhibit enhanced vascular adrenergic constriction and potentially an enhanced adrenergic activity vs. lean Zucker rats (LZR), this study tested the hypothesis that OZR exhibit an improved tolerance to progressive hemorrhage. Preliminary experiments indicated that, corrected for body mass, total blood volume was reduced in OZR vs. LZR. Anesthetized LZR and OZR had a cremaster muscle prepared for in situ videomicroscopy and had renal, splanchnic, hindlimb, and skeletal muscle perfusion monitored with flow probes. Arterial pressure, arteriolar reactivity to norepinephrine, and tissue/organ perfusion were monitored after either infusion of phentolamine or successive withdrawals of 10% total blood volume. Phentolamine infusion indicated that regional adrenergic tone under control conditions differs substantially between LZR and OZR, whereas with hemorrhage OZR exhibit decompensation in arterial pressure before LZR. Renal, distal hindlimb, and skeletal muscle perfusion decreased more rapidly and to a greater extent in OZR vs. LZR after hemorrhage. In contrast, hemorrhage-induced reductions in splanchnic perfusion in OZR lagged behind those in LZR, although a similar maximum reduction was ultimately attained. With increasing hemorrhage, cremasteric arteriolar tone increased more in OZR than LZR, and this increase in active tone was entirely due to an elevated adrenergic contribution. Norepinephrine-induced arteriolar constriction was greater in OZR vs. LZR under control conditions and during hemorrhage, with arterioles from OZR demonstrating early closure vs. LZR. These results suggest that a combination of reduced blood volume and elevated peripheral adrenergic constriction contribute to impaired hemorrhage tolerance in OZR.

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