Role of Obesity-Induced Mitochondrial Dysfunction and Inflammation in Neuropathology

Study objective: Chronic inflammation induced by obesity is suggested to be the underlying mechanism that drives pathological alterations within the body, gradually leading to multiple tissues becoming insulin resistant and developing a dysfunctional energy metabolism. Our objective is to understand the incipient changes in obesity-induced mitochondrial dysfunction and inflammation in the brain of a rodent model of obesity with chronic kidney disease (CKD), and its consequences on their cognitive status. Hypothesis: We hypothesize that chronic, systemic inflammation generated by obesity leads to pathological changes in the metabolism (insulin resistance; IR) and mitochondrial functioning of neurons and glial cells (astrocytes and microglia), which propagates a persistent inflammatory state mediated by macrophage inflammatory protein-3α (MIP3α, also known as CCL20) leading to neuropathology and cognitive deficits. Methodology and Data: Here, we used the Dahl salt-sensitive rats (SS) and its leptin receptor knockout strain (SS LepR mutant), an established model of obesity with CKD. These animals were monitored for a period of 10 weeks (8 to 18 weeks of age) for metabolic and neurological deficits: Preliminary results suggest significant elevations in parameters of obesity (plasma cholesterol, plasma triglycerides, and body weight) in SS LepR mutant rats compared to SS rats. We also monitored the changes in brain vasculature using Evan’s blue dye where our data indicate its higher infiltration across the blood-brain barrier after 18-weeks in SS LepR mutant rats compared to SS rats. Our quantification of amyloid-beta aggregates using dot-blot assay (A-11 antibody) revealed a higher load of these species in the brain of SS LepR mutant vs. SS rats after 18-weeks. Using flow-cytometry, we also found higher levels of activated microglia (CD11b + ) in the brain of obese vs. lean rats at 18-weeks. Using mitochondrial analysis, we identified that obese rats have enhanced generation of ROS, measured as a function of % electron leak, due to mitochondrial complex I and II respiration, as well as fatty acid oxidation, compared to SS rats. We also tested the cognitive status of these rodents at 18-weeks of age. Our results indicate that after testing in the Barnes’ maze for five-days, obese rats show a higher error count in finding the escape hole for the first four days, while they approach this escape less number of times upon blockage on the fifth day of trial. Our novel object recognition test shows that SS LepR mutant rats spend less time exploring the novel object in the trail phase compared to SS rats. Summary and Conclusions: These results indicate that in SS LepR mutant rats, obesity leads to deficits in brain vasculature, increases in the load of protein aggregates in the brain, and enhances activation of microglia after 18-weeks. We also see mitochondrial dysfunction in the form of increased ROS production in the brain of SS LepR mutant rats vs. SS rats. These pathological alterations may play a role in the cognitive status of SS LepR mutant rats, where they performed poorly compared to SS rats in tests that interrogated their spatial and working memory. The authors acknowledge the following funding sources: NIH/NIDDK – R01DK109133 NIH/NIA – R01AG057842 NIH/NIDDK – R56DK140968 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.