Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100 mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation.