Role of adipocyte Na,K-ATPase oxidant amplification loop in cognitive decline and neurodegeneration
Komal Sodhi,
Rebecca Pratt,
Xiaoliang Wang,
Hari Vishal Lakhani,
Sneha S. Pillai,
Mishghan Zehra,
Jiayan Wang,
Lawrence Grover,
Brandon Henderson,
James Denvir,
Jiang Liu,
Sandrine Pierre,
Thomas Nelson,
Joseph I. Shapiro
Affiliations
Komal Sodhi
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Rebecca Pratt
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Xiaoliang Wang
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Hari Vishal Lakhani
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Sneha S. Pillai
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Mishghan Zehra
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Jiayan Wang
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Lawrence Grover
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Brandon Henderson
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
James Denvir
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Jiang Liu
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Sandrine Pierre
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Thomas Nelson
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Joseph I. Shapiro
Departments of Medicine, Surgery, and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA; Corresponding author
Summary: Recent studies suggest that a western diet may contribute to clinical neurodegeneration and dementia. Adipocyte-specific expression of the Na,K-ATPase signaling antagonist, NaKtide, ameliorates the pathophysiological consequences of murine experimental obesity and renal failure. In this study, we found that a western diet produced systemic oxidant stress along with evidence of activation of Na,K-ATPase signaling within both murine brain and peripheral tissues. We also noted this diet caused increases in circulating inflammatory cytokines as well as behavioral, and brain biochemical changes consistent with neurodegeneration. Adipocyte specific NaKtide affected by a doxycycline on/off expression system ameliorated all of these diet effects. These data suggest that a western diet produces cognitive decline and neurodegeneration through augmented Na,K-ATPase signaling and that antagonism of this pathway in adipocytes ameliorates the pathophysiology. If this observation is confirmed in humans, the adipocyte Na,K-ATPase may serve as a clinical target in the therapy of neurodegenerative disorders.
