Role of Adipocyte Na,K‐ATPase Oxidant Amplification Loop in Neurodegeneration

Abstract

Background Recent studies have established that the release of adipocytokines and other bioactive mediators in obesity contributes to neurodegeneration, by crossing or altering the blood brain barrier and through effects on central neuronal tissues. Adipocyte-specific expression of Na,K-ATPase signaling antagonist, NaKtide, has been shown to ameliorate the pathophysiological consequences of obesity and improve diseased phenotype. Hypothesis We hypothesize and aim to elucidate the role of adipocyte Na,K-ATPase signaling in causing phenotypic alterations in hippocampus and motor cortex of brain in mice fed a western diet (WD), resulting in cognitive decline and neurodegeneration. Methods Transgenic mice (C57BL6 background) expressing NaKtide in a tetracycline dependent manner, specifically in adipocytes, under the control of adiponectin promoter were generated. Mice were fed a normal chow or WD, with or without doxycycline to induce adipocyte specific NaKtide expression. RNAseq analysis was performed in hippocampus and adipose tissue to characterize cellular transcriptomic changes. Results Mice fed a doxycycline diet induced NaKtide expression specifically in adipocytes and ameliorated WD induced behavioral and metabolic alterations, oxidant stress and systemic inflammation. WD induced oxidant stress, altered levels of β-amyloid and markers of neurodegeneration, including p-tau, BDNF, ERK and PSD95, in hippocampus and motor cortex. These changes were concomitant with altered adipocyte phenotype. Alterations in brain parts and adipocytes were reverted by NaKtide. RNAseq analysis in WD fed transgenic mice showed large scale differential gene expression as well as modulation of several biological pathways in hippocampus, visceral and subcutaneous adipose tissue, which were attenuated by doxycycline induced adipocyte specific NaKtide expression. Conclusion These data suggest that adipocyte Na,K-ATPase signaling mediated oxidant stress results in cellular changes that modulates hippocampus and motor cortex function causing subsequent cognitive decline and neurodegeneration. The adipocyte specific antagonism of Na,K-ATPase by NaKtide rescue these changes in brain and improve neurodegenerative phenotype. To the best of our knowledge, this is the first study to elucidate a role of adipocytes in cognitive decline and neurodegeneration. Understanding the role of the adipocyte Na/K-ATPase signaling in the pathogenesis of neurodegeneration could lead to the development of new therapeutic strategies in addition to NaKtide, to fight neurodegenerative disorders.