Metabolic Stress Leads to Neuro‐inflammation and Mild Cognitive Impairment Prior to Development of Hyperglycemia: Role of Autophagy Suppression
Authors: Fakih Walaa Kamel , Mroueh Ali Kamel , Salah Hussein F. , Obeid Makram F. , Kobeissy Firas F. , Darwish Hala , El‐Yazbi Ahmed F. 
Published: June 2021

Metabolic disorders, usually resulting from excessive caloric intake, not only confer an increased risk of type 2 diabetes and cardiovascular disease, but also trigger neuro‐inflammation and cognitive impairment. Significantly, suppression of autophagy, which is a rescue mechanism that processes the accumulated malformed proteins, is another consequence of increased caloric intake. Indeed, this would be particularly relevant in the brain where deficient autophagy may cause neurodegeneration. We examined whether reduced autophagy has a role in the neuro‐behavioral deficit associated with metabolic stress. For this purpose, we used high‐calorie (HC) diet‐fed rat model developed in our laboratory. Twelve weeks of HC feeding lead to hyperinsulinemia, in addition to vascular and cardiac autonomic anomalies, but without obesity and hyperglycemia that develop later in the course of treatment. Behavioral testing (Morris water maze, spontaneous object recognition, temporal order memory, and open field test) was used to assess the effects on learning, memory and anxiety‐like behavior. Pressure myography of rat middle cerebral artery was used to examine the blood flow autoregulatory function of the cerebrovascular bed. Markers of autophagy, apoptosis, microglial activation, and oxidative stress were examined in the hippocampus by western blotting and immunohistochemistry. HC‐fed rats showed slight deficiencies in hippocampus‐related activities like spatial learning and memory, spontaneous object and temporal order memory compared to those receiving regular chow. The increased time spent in the center of the open field test indicated that control rats had more willingness to explore compared to HC‐fed rats. There were no differences in the total distance travelled between both groups. The behavioral deficit in HC‐rats was associated with an increased cerebrovascular tone potentially leading to brain hypoxia. Molecular examination revealed increased reactive oxygen species production in the hippocampus of HC‐fed rats together with increased microglial activation apparent as upregulated CD68 staining. A hippocampal inflammatory response in these rats was detected by increased IL‐1β expression. Accumulation of LC3 and p62 proteins together with a decline in beclin‐1 indicated autophagy suppression in HC‐fed rat hippocampus. Increased TUNEL‐stained nuclei in this rat group compared to controls might imply that failure of clearance of miscoiled protein products triggered hippocampal cell death. As such, it appears that early stages of metabolic stress could lead to subtle behavioral impairment triggered by hippocampal neuronal inflammation and cell death potentially due to suppression of autophagy.Support or Funding InformationSupported by CNRS‐L grants #010817 and AUBFM grant # 320148This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.