Summary: New research reveals how adipocytes (fat cells) contribute to cognitive decline and increased risk of neurodegeneration. Using genetically modified mouse models, scientists show that oxidative stress driven by a Western diet activates an Na,K-ATPase oxidant amplification loop in adipocytes, raising inflammatory cytokines and altering hippocampal protein markers tied to memory and cognition.
Source: Marshall University
New findings published this week provide insight into the role of fat cells in cognitive decline and neurodegeneration, highlighting the Na,K-ATPase oxidant amplification loop as a key mechanism discovered by researchers at Marshall University.
Published in iScience, the study demonstrates that adipocytes help regulate systemic processes that affect brain function, producing changes that impair memory and cognition in mice.
The investigators found that activation of the Na,K-ATPase oxidant amplification loop alters expression of proteins both in adipose tissue and in the hippocampus, a brain region essential for learning and memory. These molecular changes are associated with worsened brain function and signs of neurodegeneration. The data suggest that targeting adipocyte Na,K-ATPase signaling could reduce inflammation and protect cognitive function.
“We sought to show that Na,K-ATPase signaling within adipocytes plays a central role in driving changes in specific brain regions—most notably the hippocampus—that underlie memory and cognitive dysfunction,” said senior author Joseph I. Shapiro, M.D., professor and dean of the Marshall University Joan C. Edwards School of Medicine.
The team used a genetically engineered mouse model that expresses the peptide NaKtide specifically in adipocytes. NaKtide antagonizes the signaling function of Na,K-ATPase. Adipocyte-specific expression of NaKtide improved the dysfunctional phenotype of fat cells and restored aspects of hippocampal function associated with memory and cognition.
Feeding mice a Western-style diet induced oxidative stress and increased production of inflammatory cytokines localized to adipocytes. These adipose-derived inflammatory signals coincided with altered protein markers and gene expression patterns in the hippocampus consistent with impaired cognitive function.
“A Western diet drives oxidative stress and adipocyte dysfunction through Na,K-ATPase signaling, producing systemic inflammation and behavioral and biochemical changes in the brain,” said Komal Sodhi, M.D., first author and associate professor of surgery and biomedical sciences at the Joan C. Edwards School of Medicine.
When NaKtide expression was restricted to adipocytes, the researchers observed reversal of many diet-induced changes: adipose tissue phenotype improved, circulating inflammation declined, and markers of neurodegeneration and cognitive impairment in the hippocampus were mitigated. The results support a model in which adipocyte Na,K-ATPase signaling contributes to diet-related cognitive decline and identify adipocyte-specific NaKtide as a potential therapeutic strategy in this pathway.
This work builds on foundational studies by the late Zijian Xie, Ph.D., former director of the Marshall Institute for Interdisciplinary Research. Continued investigation will determine whether these mouse-model findings translate to humans and whether adipocyte Na,K-ATPase can serve as a viable clinical target in neurodegenerative diseases.
In addition to Shapiro and Sodhi, coauthors include Rebecca Pratt, Xiaoliang Wang, Hari Vishal Lakhani, Sneha S. Pillai, Mishghan Zehra, Jiayan Wang, Lawrence Grover, Brandon Henderson, James Denvir, Jiang Liu, Sandrine Pierre, and Thomas Nelson, all affiliated with Marshall University.
Funding: This research was supported by National Institutes of Health grants 1R15HL150721 (to K.S.), the NIH Bench-to-Bedside award through the Office of Research on Women’s Health (ORWH) 736214 (to K.S. and J.I.S.), the BrickStreet Foundation (to J.I.S.), and the Huntington Foundation, Inc. (J.I.S.). Additional institutional support came from WV-INBRE (NIH/NIGMS P20GM103434), the COBRE ACCORD (1P20GM121299), and the WV-CTSI (2U54GM104942).
About this diet and cognition research news
Author: Sheanna Spence
Source: Marshall University
Contact: Sheanna Spence – Marshall University
Image: The image is in the public domain
Original Research: Open access. “Role of Adipocyte Na,K-ATPase Oxidant Amplification Loop in Cognitive Decline and Neurodegeneration” by Joseph I. Shapiro et al., published in iScience.
Abstract
Role of Adipocyte Na,K-ATPase Oxidant Amplification Loop in Cognitive Decline and Neurodegeneration
Highlights
- Adipocytes can drive phenotypic changes that contribute to neurodegeneration via an Na,K-ATPase–dependent oxidant amplification loop (NKAL).
- Adipocyte-specific expression of NaKtide inhibits NKAL and improves systemic metabolic and inflammatory homeostasis.
- NaKtide restores healthier adipocyte phenotype and reduces markers associated with neurodegeneration in the hippocampus.
- NaKtide modulates the genomic profiles of both hippocampus and adipose tissue in mice fed a Western diet, reversing many diet-induced alterations.
Summary
Accumulating evidence links Western-style diets to increased risk of clinical neurodegeneration and dementia. In murine models, adipocyte-specific expression of NaKtide, an antagonist of Na,K-ATPase signaling, reduces the pathological consequences of diet-induced obesity and organ dysfunction.
In this study, a Western diet produced systemic oxidative stress and activated Na,K-ATPase signaling in both brain and peripheral tissues. The diet increased circulating inflammatory cytokines and triggered behavioral and biochemical brain changes consistent with neurodegeneration.
Using a doxycycline-regulated on/off system to drive adipocyte-specific NaKtide expression, researchers showed that antagonizing Na,K-ATPase signaling in fat cells ameliorated the inflammatory, behavioral, and molecular effects induced by the Western diet. These findings indicate that enhanced Na,K-ATPase signaling in adipocytes is a mechanistic link between diet, systemic inflammation, and cognitive decline.
If replicated in human studies, adipocyte Na,K-ATPase signaling could represent a novel therapeutic target for preventing or treating diet-related cognitive impairment and neurodegenerative disorders.