{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:33:10Z","timestamp":1789763590830,"version":"4.0.1"},"reference-count":85,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T00:00:00Z","timestamp":1579392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oxidative stress and insulin resistance play major roles in numerous neurodegenerative diseases, including Alzheimer\u2019s disease (AD). A high-fat diet induces obesity-associated oxidative stress, neuronal insulin resistance, microglial activation, and neuroinflammation, which are considered important risk factors for neurodegeneration. Obesity-related metabolic dysfunction is a risk factor for cognitive decline. The present study aimed to elucidate whether chronic consumption of a high-fat diet (HFD; 24 weeks) can induce insulin resistance, neuroinflammation, and amyloid beta (A\u03b2) deposition in mouse brains. Male C57BL\/6N mice were used for a high-fat diet (HFD)-induced pre-clinical model of obesity. The protein expression levels were examined via Western blot, immunofluorescence, and the behavior analysis was performed using the Morris water maze test. To obtain metabolic parameters, insulin sensitivity and glucose tolerance tests were performed. We found that metabolic perturbations from the chronic consumption of HFD elevated neuronal oxidative stress and insulin resistance through adiponectin receptor (AdipoR1) suppression in HFD-fed mice. Similarly, our in vitro results also indicated that knockdown of AdipoR1 in the embryonic mouse hippocampal cell line mHippoE-14 leads to increased oxidative stress in neurons. In addition, HFD markedly increased neuroinflammatory markers\u2019 glial activation in the cortex and hippocampus regions of HFD mouse brains. More importantly, we observed that AdipoR1 suppression increased the amyloidogenic pathway both in vivo and in vitro. Furthermore, deregulated synaptic proteins and behavioral deficits were observed in the HFD mouse brains. Taken together, our findings suggest that excessive consumption of an HFD has a profound impact on brain function, which involves the acceleration of cognitive impairment due to increased obesity-associated oxidative stress, insulin resistance, and neuroinflammation, which ultimately may cause early onset of Alzheimer\u2019s pathology via the suppression of AdipoR1 signaling in the brain.<\/jats:p>","DOI":"10.3390\/cells9010249","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T03:04:43Z","timestamp":1579575883000},"page":"249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer\u2019s Like Pathology in Mice Brain"],"prefix":"10.3390","volume":"9","author":[{"given":"Jong Ryeal","family":"Hahm","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Gyeongsang National University Hospital and Institute of Health Sciences and Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeung Hoon","family":"Jo","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahat","family":"Ullah","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Woo","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong Ok","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Park, S.B., Kang, J.Y., Kim, J.M., Park, S.K., Yoo, S.K., Lee, U., Kim, D.O., and Heo, H.J. 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