Neuroprotective effect of treadmill exercise against blunted brain insulin signaling, NADPH oxidase, and Tau hyperphosphorylation in rats fed a high-fat diet

Obesity induces oxidative stress by causing hyperglycemia and insulin resistance, while contributing to cognitive and memory decline by inducing insulin resistance in the brain and hyperphosphorylation of Tau proteins. We aimed to investigate the effects of treadmill exercise in improving these obesity-induced pathological phenomena. Sprague-Dawley rats aged 20 weeks were fed a high-fat diet (HFD) for 20 weeks to induce obesity. The rats were subsequently subjected to treadmill exercise (progressively increasing load intensity) for 8 weeks. The rats were divided into three groups: normal diet-control (n = 15), HFD-control (n = 15), and HFD-treadmill exercise (n = 15). We performed water maze and passive avoidance tests and assessed weight, area under the curve, homeostatic model assessment of insulin resistance, and abdominal visceral fat/body weight. Western blot was used to examine protein expression related to brain insulin signaling, tau hyperphosphorylation, and NADPH oxidase, and immunohistochemistry was performed to examine the immunoreactivity of p-Tau (Ser 202/Thr 205) and p22-phox. Treadmill exercise effectively rescued brain insulin signaling, hyperphosphorylation and aggregation of Tau protein, and NADPH oxidase activation in the high fat diet group. Furthermore, it improved insulin resistance inhibitors, decreased abdominal fat mass, inhibited weight gain, and rescued learning and memory. Obesity-induced insulin resistance contributes to cognitive decline, such as reduced learning and memory, but physical activity, such as treadmill exercise, was found to have a positive effect on brain function by improving thesepathological phenomena. Therefore, we suggest that treadmill exercise must be considered in the prevention and treatment of metabolic and neurodegenerative diseases.