Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability

Menopausal women are at greater risk of developing metabolic syndrome with reduced endothelial nitric oxide synthase (eNOS) activity. Hormone replacement therapy increases eNOS activity and normalizes some characteristics of metabolic syndrome. We hypothesized that nitric oxide (NO) supplementation should have a therapeutic effect on this syndrome. We examined the effect of dietary nitrite in a mouse model with postmenopausal metabolic syndrome induced by ovariectomy (OVX) and a high fat diet (HF). C57BL/6 female mice were divided into five groups, sham+normal fat diet (NF), sham+ HF, OVX+HF with or without sodium nitrite (50 mg and 150 mg/l) in the drinking water. Daily food intake and weekly body weight were monitored for 18 wk. OVX and HF significantly reduced plasma levels of nitrate/nitrite (NOx), and mice developed obesity with visceral hypertrophic adipocytes and increased transcriptional levels of monocyte chemoattractant protein-1, TNF-α, and IL-6 in visceral fat tissues. The proinflammatory state in the adipocytes provoked severe hepatosteatosis and insulin resistance in OVX+HF group compared with sham+NF group. However, dietary nitrite significantly suppressed adipocyte hypertrophy and transcriptions of proinflammatory cytokines in visceral fat in a dose-dependent manner. The improvement of visceral inflammatory state consequently reversed the hepatosteatosis and insulin resistance observed in OVX+HF mice. These results suggest that an endogenous NO defect might underlie postmenopausal metabolic syndrome and that dietary nitrite provides an alternative source of NO, subsequently compensating for metabolic impairments of this syndrome.

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Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Features of Metabolic Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2006.075176 ◽

2007 ◽

Vol 53 (1) ◽

pp. 91-97 ◽

Cited By ~ 29

Author(s):

José L González-Sánchez ◽

María T Martínez-Larrad ◽

María E Sáez ◽

Carina Zabena ◽

María J Martínez-Calatrava ◽

...

Keyword(s):

Nitric Oxide ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Genetic Variation ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Hdl Cholesterol ◽

Enos Gene ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Abstract Background: The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene–null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans. Methods: We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81, 95% confidence interval (CI) 1.15–2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01–2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P = 0.026). Conclusions: Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations.

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Metabolic aspects of the relationship of asthma and obesity

Obesity and metabolism ◽

10.14341/omet9578 ◽

2019 ◽

Vol 15 (4) ◽

pp. 9-14 ◽

Cited By ~ 3

Author(s):

Oxana Y. Kytikova ◽

Marina V. Antonyuk ◽

Tatyana A. Gvozdenko ◽

Tatyana Р. Novgorodtseva

Keyword(s):

Nitric Oxide ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Common Mechanism ◽

The Metabolic Syndrome ◽

Duration Of Hospitalization ◽

Mechanisms Of Formation ◽

Relationship Of ◽

The Relationship

Asthma and obesity are serious medical and social world problems, and their combined course is characterized by a decrease in the quality of life, an increase in the frequency and duration of hospitalization. The present review summarizes the current views on the mechanisms of formation of asthma phenotype combined with obesity, role of leptin and adiponectin imbalance in the development of systemic inflammation in obesity in the pathophysiology of asthma, its interrelations with metabolic syndrome. We present data that shows that syndrome is closely related not only to the debut of asthma, but also to a decrease in its control. Along with obesity, the role of other components of metabolic syndrome, in particular insulin resistance, as a predictor of asthma development is considered. Insulin resistance may be the most likely factor in the relationship between asthma and obesity, independent of other components of the metabolic syndrome. Insulin resistance associated with obesity can lead to disruption of nitric oxide synthesis. We reveal common mechanism of metabolic disorders of nitric oxide and arginine in metabolic syndrome and asthma and show that insulin resistance treatment can be therapeutically useful in patients with asthma in combination with obesity.

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Angiostatin Does Not Contribute to Skeletal Muscle Microvascular Rarefaction with Low Nitric Oxide Bioavailability

Microcirculation ◽

10.1080/10739680601131242 ◽

2007 ◽

Vol 14 (2) ◽

pp. 145-153 ◽

Cited By ~ 7

Author(s):

Jefferson C. Frisbee ◽

Julie Balch Samora ◽

David P. Basile

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Nitric Oxide Bioavailability ◽

Microvascular Rarefaction

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Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00114.2005 ◽

2005 ◽

Vol 289 (2) ◽

pp. R307-R316 ◽

Cited By ~ 75

Author(s):

Jefferson C. Frisbee

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Microvessel Density ◽

Gastrocnemius Muscle ◽

Oxidant Stress ◽

Zucker Rats ◽

Metabolic Demand ◽

The Metabolic Syndrome ◽

Nitric Oxide Bioavailability

This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for ∼4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with Nω-nitro-l-arginine methyl ester (l-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.

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Abstract 19179: Effects of Systemic Insulin Resistance on Redox State and Endothelial Nitric Oxide Bioavailability in the Human Vascular Wall

Circulation ◽

10.1161/circ.132.suppl_3.19179 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Ioannis Akoumianakis ◽

Marios Margaritis ◽

Constantinos Psarros ◽

Laura Herdman ◽

Alexios Antonopoulos ◽

...

Keyword(s):

Nitric Oxide ◽

Insulin Resistance ◽

Endothelial Function ◽

Redox State ◽

Ex Vivo ◽

Diabetic Patients ◽

Model Assessment ◽

Systemic Insulin Resistance ◽

Increased Risk ◽

Nitric Oxide Bioavailability

Background: Insulin resistance (IR) and diabetes mellitus (DM) are associated with increased risk of cardiovascular disease. We explored the specific effects of insulin resistance on vascular redox state and endothelial function in non-diabetic patients with coronary atherosclerosis. Methods: The study population consisted of 383 patients undergoing coronary bypass surgery (CABG). Endothelial function was estimated using non-invasive imaging (brachial Flow-Mediated Dilatation -FMD) preoperatively. During surgery, segments of human saphenous vein (SV)were obtained and used to quantify nitric oxide bioavailability (ex vivo vasorelaxations in response to acetylcholine) and NADPH oxidase-derived superoxide (O2-) by lucigenin chemiluminescence (using NADPH at 100μM). Glucose and insulin were measured in plasmas for calculation of HOMA-IR, the homeostatic model assessment of IR status. Results: The presence of IR (HOMA-IR>2.9) was associated with impaired FMD (A), reduced vasorelaxations of human vessels in response to acetylcholine (B) and elevated vascular O2- generation (C). Conclusions: IR is associated with impaired endothelial function and increased oxidative stress in human vessels. This is the first study demonstrating a direct effect of systemic insulin resistance on key mechanisms of atherogenesis in human vessels, highlighting it as a specific therapeutic target in non-diabetic patients with atherosclerosis.

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