Endothelial Nitric Oxide Synthase (eNOS) Knockout Mice Have Defective Mitochondrial β-Oxidation

Gouill, Eric Le; Jiménez, María; Binnert, Christophe; Jayet, Pierre‐Yves; Thalmann, Sébastien; Nicod, Pascal; Scherrer, Urs; Vollenweider, Péter

doi:10.2337/db06-1228

Cited by 106 publications

(98 citation statements)

References 28 publications

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“…More recently, Augeri et al [2] found that the -786C allele is associated with blood pressure reductions immediately following low to moderate intensity aerobic exercise. On the other hand, eNOS(-/-) mice had significantly lower oxygen consumption compared with their wild-type counterparts [14]. Thus, more research, using mechanistic approaches (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…This molecule also modulates the kinetics of oxygen consumption during exertion [29]. Recent research demonstrated that eNOS(-/-) mice had significantly lower oxygen consumption and defective mitochondria compared with non-transgenic controls, as evidenced by decreased betaoxidation [14]. For the abovementioned reasons, the NOS3 gene is a candidate to be associated with sports performance.…”

Section: Introductionmentioning

confidence: 99%

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The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

et al. 2012

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The NOS3-786 T/C polymorphism (rs2070744) is a candidate to explain individual variations in sports related phenotypes. We determined the genotype and allele frequency of NOS3-786 T/C in a group of 60 male professional elite soccer players.Their results were compared with those of 100 world-class endurance athletes, 53 elite power athletes, and 100 sedentary, healthy men (controls) of the same Caucasian (Spanish) origin. There were significant differences in genotype frequencies between soccer players, controls, endurance and power elite athletes (all P≤0.02). These results were confirmed when we analysed allelic frequencies (all P<0.01). The likelihood of having the C allele was higher in soccer players compared with (i) controls [odds ratio (OR), 2.165, 95% confidence interval (CI): 1.362-3.441], (ii) endurance athletes (OR:1.879, 95%CI: 1.184-2.984), and (iii) power athletes (OR: 4.032, 95%CI: 2.307-7.047). In conclusion, the -786C allele is associated with the status of being an elite soccer player, compared with non-athletic controls and also with elite endurance and power athletes. More research is needed in other groups of elite soccer players in order to replicate the results of the present study.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

et al. 2012

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“…180 Increased expression of eNOS by physical activity may stimulate mitochondrial biogenesis. 49,181 Moderate-intensity physical activity combined with weight loss improves insulin sensitivity through increasing skeletal muscle electron transport chain activity and increasing mitochondrial cristae (without changing mtDNA content). 182 Age-associated reduction in expression of mitochon- Figure 6.…”

Section: Exercisementioning

confidence: 99%

Role of Mitochondrial Dysfunction in Insulin Resistance

Kim

Wei

Sowers

2008

Circulation Research

821

642

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Abstract-Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue. (Circ Res. 2008;102:401-414.)Key Words: mitochondrial dysfunction Ⅲ insulin resistance Ⅲ cardiovascular disease T here are at least 47 million people in the United States who have the cardiometabolic syndrome, a precursor to diabetes and subsequent cardiovascular complications. 1 Furthermore, the development of insulin resistance, the cardinal feature of the cardiometabolic syndrome, is associated with increased tissue renin-angiotensin system activity and increasingly appears to be a nexus between components of the syndrome. 2,3 The metabolic actions of insulin maintain glucose homeostasis by promoting glucose uptake in skeletal muscle and suppressing glucose production in the liver. Insulin resistance is typically defined as decreased sensitivity to these metabolic actions of insulin. Insulin-resistant individuals are at higher risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular disease compared with Original received October 12, 2007; revision received December 17, 2007; accepted January 9, 2008 Figure 2). 5-7 Furthermore, we and others have shown that blockade of the AT 1 R reduces oxidative stress and mitochondrial structure and functional abnormalities in rodent models of excessi...

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“…Interestingly, mice with homozygous inactivation of the eNOS gene (eNOS Ϫ/Ϫ mice) show features of the metabolic syndrome, including obesity, insulin resistance, hyperlipidemia, and hypertension (4, 9). Although the underlying mechanisms of these metabolic derangements have not been clearly elucidated, recent studies have suggested that eNOS plays an important role in mitochondrial biogenesis (30, 42); eNOS Ϫ/Ϫ mice showed mitochondrial dysfunction and significant intramyocellular lipid accumulation in skeletal muscle (20). Insulin resistance in eNOS Ϫ/Ϫ mice may arise from impaired mitochondrial oxidation of fatty acid and the resulting intracellular accumulation of fat moieties, such as long-chain acylCoA esters, diacylglycerol, and ceramide, that interfere with insulin signaling (6,26,28).…”

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confidence: 99%

eNOS plays a major role in adiponectin synthesis in adipocytes

Koh

Kim

Ranjan

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Nitric oxide (NO) stimulates mitochondrial biogenesis. We recently reported that adiponectin synthesis is regulated by mitochondrial function in adipocytes. This study was undertaken to test the hypothesis that endothelial NO synthase (eNOS) plays an important role in adiponectin synthesis by producing NO and enhancing mitochondrial function in adipocytes. We examined the effects of eNOS knockdown on adiponectin synthesis in 3T3-L1 adipocytes and also examined plasma adiponectin levels and the mitochondria in adipose tissue of eNOS knockout (eNOS Ϫ/Ϫ ) mice with and without chronic administration of a NO donor. In cultured 3T3-L1 adipocytes, eNOS siRNA decreased rosiglitazone-induced adiponectin secretion, which was associated with decreases in mitochondrial proteins and biogenesis factors. Plasma adiponectin concentrations were reduced in adult eNOS Ϫ/Ϫ mice compared with age-matched wild-type mice. Mitochondrial contents in adipose tissue were reduced in eNOS Ϫ/Ϫ mice, and this was associated with decreased expression of mitochondrial biogenesis factors, increased levels of 8-hydroxyguanosine, a biomarker of oxidative stress, and morphological abnormalities in mitochondria. Rosiglitazone-induced increases in adiponectin expression and mitochondrial content were also reduced significantly in eNOS Ϫ/Ϫ mice. Chronic administration of a NO donor reversed mitochondrial abnormalities and increased adiponectin expression in adipose tissue of eNOS Ϫ/Ϫ mice. eNOS plays an important role in adiponectin synthesis in adipocytes by increasing mitochondrial biogenesis and enhancing mitochondrial function. endothelial nitric oxide synthase; mitochondrial biogenesis; oxidative stress; nitric oxide ADIPONECTIN, ONE OF THE ADIPOCYTE HORMONES, has many favorable effects on metabolism, including improvement of insulin action and reduction of atherosclerotic processes and cancer (1,13,17,18,36). Unlike other adipocytokines, the plasma level of adiponectin is reduced in obese individuals due to selective suppression of its synthesis in adipocytes. We recently reported that mitochondrial function is essential for adiponectin synthesis in adipocytes, and mitochondrial dysfunction in adipose tissue explains decreased adiponectin synthesis in obesity (16). This study demonstrated that plasma adiponectin levels and adiponectin expression in adipose tissue were profoundly reduced in obese db/db mice, which was associated with decreased adipose tissue mitochondrial content and function. In addition, rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist, normalized plasma adiponectin levels and adiponectin expression in obese db/db mice by reversing the changes in mitochondrial content and function in adipose tissue.Nitric oxide (NO) has been shown to stimulate mitochondrial biogenesis (30, 31), and evidence has accumulated that NO synthases play a crucial role in energy metabolism (14,24). Among the known NO synthases, endothelial NO synthase (eNOS) was identified originally as playing an important role in the regu...

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Endothelial Nitric Oxide Synthase (eNOS) Knockout Mice Have Defective Mitochondrial β-Oxidation

Cited by 106 publications

References 28 publications

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

The C Allele in NOS3 -786 T/C Polymorphism is Associated with Elite Soccer Player's Status

Role of Mitochondrial Dysfunction in Insulin Resistance

eNOS plays a major role in adiponectin synthesis in adipocytes

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