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The Adipocyte Na/K-ATPase Oxidant Amplification Loop is the Central Regulator of Western Diet-Induced Obesity and Associated Comorbidities

Published Date: 2019-06-24      Source: http://www.unitedwellhk.com/index.php/news/index/id/22.html


Abstract

Obesity has become a worldwide epidemic. We have previously reported that systemic administration of pNaKtide which targets the Na/K-ATPase oxidant amplification loop (NKAL) was able to decrease systemic oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play a central role in the development of obesity and its related comorbidities, we examined whether lentiviral-mediated adipocyte-specific expression of NaKtide, a peptide derived from the N domain of the alpha1 Na/K-ATPase subunit, could ameliorate the effects of the WD. C57BL6 mice were fed a WD, which activated Na/K-ATPase signaling in the adipocytes and induced an obese phenotype and caused an increase in plasma levels of leptin, IL-6 and TNFα. WD also decreased locomotor activity, expression of the D2 receptor and tyrosine hydroxylase in brain tissue, while markers of neurodegeneration and neuronal apoptosis were increased following the WD. Selective adipocyte expression of NaKtide in these mice fed a WD attenuated all of these changes including the brain biochemical alterations and behavioral adaptations. These data suggest that adipocyte derived cytokines play an essential role in the development of obesity induced by a WD and that targeting the adipocyte NKAL loop may serve as an effective therapeutic strategy.

 

Introduction

Obesity is a major international health challenge as it is often associated with other comorbidities including (but not limited to) metabolic syndrome, cardiovascular diseases, chronic kidney disease, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. It is estimated that by the year 2030, 38% of the world’s adult population will be overweight and 20% will be obese. Although traditionally the adipocyte had been thought to play a passive role in the process of obesity, recent studies have established adipocyte malfunction as playing a causative role in the pathogenesis of obesity, associated systemic oxidant stress and the comorbidities of obesity including insulin resistance, accelerated cardiovascular disease and NASH. Evidence suggests that deranged mitochondrial function and chronic inflammation in the adipocytes further contribute towards the pathogenesis of obesity.


Our group has demonstrated that the Na/K-ATPase functions as a scaffolding protein, affecting a signal cascade that also serves to amplify oxidants in a feed forward manner. Activated Na/K-ATPase signaling has been demonstrated in adipose, hepatic, renal, and cardiac tissues, thus implying a role for Na/K-ATPase signaling in various disease models. Specifically, we have demonstrated that reactive oxygen species (ROS) can both activate this Na/K-ATPase signal cascade as well as generate additional ROS through downstream consequences of this pathway. NaKtide, a specific peptide antagonist of Src kinase, was derived from the α1 subunit of the NaK-ATPase, consisting of Ser 415 to Gln 434. NaKtide or a cell permeant derivative, pNaKtide which was created by merging NaKtide with a 13 amino acid TAT leading sequence, prevents the activation of Src which is normally regulated by the α1 subunit of the Na/K-ATPase. Since we have demonstrated that systemic administration of pNaKtide was able to reduce oxidative stress, obesity and atherosclerosis induced by a western diet composed of high fat and supplemental fructose, we were interested in using this molecular strategy to examine the specific tissues involved in the pathogenesis of obesity.


Lentiviral vectors have evolved over the last decade as a promising approach to target a gene of interest using a promoter for a specific cell type. Utilization of the lentiviral vector has been safe and highly effective in experimental models. We therefore chose this strategy to test the hypothesis that adipocyte oxidant stress caused by activation of adipocyte Na/K-ATPase signaling might play a central role in the development and maintenance of obesity and its associated comorbidities.


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