Overexpression of Endothelial Nitric Oxide Synthase Prevents Diet-Induced Obesity and Regulates Adipocyte Phenotype

Abstract

Rationale Endothelial dysfunction is a characteristic feature of diabetes and obesity in animal models and humans. Deficits in nitric oxide production by endothelial nitric oxide synthase (eNOS) are associated with insulin resistance, which is exacerbated by high fat diet. Nevertheless, the metabolic effects of increasing eNOS levels have not been studied. Objective The current study was designed to test whether overexpression of eNOS would prevent diet-induced obesity and insulin resistance. Methods and Results In db/db mice and in high fat-fed wild-type (WT) C57BL/6J mice, the abundance of eNOS protein in adipose tissue was decreased without significant changes in eNOS levels in skeletal muscle or aorta. Mice overexpressing eNOS (eNOS-TG mice) were resistant to diet-induced obesity and hyperinsulinemia, although systemic glucose intolerance remained largely unaffected. In comparison with WT mice, high fat-fed eNOS-TG mice displayed a higher metabolic rate and attenuated hypertrophy of white adipocytes. Overexpression of eNOS did not affect food consumption or diet-induced changes in plasma cholesterol or leptin levels, yet plasma triglycerides and fatty acids were decreased. Metabolomic analysis of adipose tissue indicated that eNOS overexpression primarily affected amino acid and lipid metabolism; subpathway analysis suggested changes in fatty acid oxidation. In agreement with these findings, adipose tissue from eNOS-TG mice showed higher levels of PPAR-α and PPAR–γ gene expression, elevated abundance of mitochondrial proteins, and a higher rate of oxygen consumption. Conclusions These findings demonstrate that increased eNOS activity prevents the obesogenic effects of high fat diet without affecting systemic insulin resistance, in part, by stimulating metabolic activity in adipose tissue.

Exhaled Breath Condensate Nitrate Levels are Inversely Associated with the Body Mass Index of Patients without Respiratory Disease

“…ADMA impairs endothelial NOS function and contributes to the cardiovascular complications often seen with obesity [20]. Moreover, recent findings suggest that eNOS impairment may also contribute to obesity by attenuating or preventing increases in metabolic activity in the adipose tissue [56]. Ware, et al [43] recently found significantly lower citrulline plasma levels in ARDS compared to non-ARDS patients.…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…This has long been hypothesized for angiotensin II [59], and more recently demonstrated for prostanoids [60] and NO itself [61]. The interference of ET-1 on metabolic function has been deeply investigated: ET-1 infusion results in hyperinsulinemia and insulin resistance in vivo [62], and chronically elevated ET-1 levels may contribute to desensitization of metabolic signaling pathways on adipocytes [63].…”

Opposing Roles of Nitric Oxide and Rho-Kinase in Lipid Metabolism in Mice

“…On the other hand, eNOS inactivation has been thought to be up-stream mechanisms of metabolic disorders (Duplain et al 2001;Nakata et al 2008;Sansbury et al 2012). Both eNOS −/− and n/i/eNOSs −/− mice show the phenotypes of metabolic syndrome (Duplain et al 2001;Nakata et al 2008), while in endothelium-specific eNOS transgenic mice, diet-induced hypercholesterolemia was prevented (Sansbury et al 2012). These findings suggest that eNOS inactivation is up-stream of metabolic disorder, but not the simple result of endothelial dysfunction.…”

“…hypertension, diabetes and dyslipidemia) further accelerate endothelial dysfunction (Shimokawa 1999). eNOS is thought to be an up-stream molecule of metabolic disorder, because either eNOS −/− mice or n/i/eNOSs −/− mice showed the phenotypes of metabolic syndrome (Duplain et al 2001;Nakata et al 2008) and conversely, in endothelium-specific eNOS transgenic mice, diet-induced hypercholesterolemia was prevented (Sansbury et al 2012). Moreover, activity of sterol regulatory element-binding protein (SREBP)-2, a transcriptional factor for cholesterol metabolism and expression of lowdensity lipoprotein (LDL) receptor were decreased in highfat diet (HFD)-fed n/i/eNOSs −/− mice with resultant severe dyslipidemia (Yatera et al 2010).…”