Exercise Mitigates Cognitive Impairment in High Fat Diet Fed Mice via Metabolic and Epigenetic Dysregulation

Abstract

High‐fat diet (HFD) induced obesity is a risk factor for cognitive impairment. The average American diet is rich in saturated fats, refined sugars and cholesterol. Excessive intake of this diet may lead to the disruption of neuropeptide expression within the brain, in turn causing metabolic and epigenetic alterations. According to clinical recommendation, regular practice of exercise (EX) has been found to be effective in treating obesity and obesity‐related conditions, as well as can reduce the risk of cognitive degeneration. However, the role of exercise on brain functions needs to be further explored. In the current study, we aimed to investigate the beneficial effects of regular exercise accompanied by a HFD with special emphasis on metabolic dysregulation, neuroinflammation and epigenetic modulation. In our study, 8–10 week old male/female C57BL/6 wild‐type mice were grouped as follows according to their diet and exercise (EX) category: (i) standard nonfat diet NFD (6%); (ii) NFD + EX; (iii) HFD (42%); (iv) HFD + EX. The NFD and HFD were given for a period of three months. The selected mice were exercised for this 12 week duration on a treadmill, with controlled speeds of 7 meters/min the first week, 9 meters/min the second week and 11 meters/min the following weeks for a total of 330 meters each day, 5 days per week. After every 110 meters, the mice were given rest for 10 minutes. Active monitoring was performed to ensure movement of the mice. To assess the memory‐related behavior of the experimental mice, the Novel Object Recognition Test (NORT), Passive Avoidance Task (PAT) and two Y‐maze tests (Spontaneous Alternation and Two‐Trial Recognition) were performed. At the end of each experimental protocol, the mice were sacrificed and the brains were isolated for the assessment of proteins, mRNA expression as well as brain tissue imaging of metabolic indicators Glucose Transporters 1 and 4 (GLUT‐1, GLUT‐4), neuronal activity markers Synapse‐Associated Proteins 90 and 97 (SAP‐90, SAP‐97), inflammatory indicator Tumor Necrosis Factor Alpha (TNF‐α) and epigenetic markers including, Sirtuin 1 (SIRT‐1), Histone Deacetylase 1 (HDAC‐1) and Brain‐Derived Neurotrophic Factor (BDNF) via Western Blot, real‐time PCR and Immunohistochemistry. Behavioral test data suggest a significant improvement in cognitive function in the HFD fed group treated with exercise, as compared to the non‐exercised HFD fed group. We found significant downregulation in neuronal, epigenetic and metabolic protein expression of SAP‐90, SAP‐97, BDNF, SIRT‐1, GLUT‐1 and GLUT‐4 and up‐regulation in inflammatory protein expression of TNF‐α in mice consuming a HFD. Interestingly, exercised prevented the detrimental effects of a HFD. In conclusion, our results indicated numerous beneficiary effects of exercise over cognitive, metabolic, neuroinflammatory and epigenetic alterations in obesity induced by a HFD. Thus, the regulatory role of exercise in cognitive and brain functions in the obese condition cannot be underestimated.Support or Funding InformationThis work is financially supported by the National Institutes of Health grants AR‐067667 and HL‐107640‐NT and are greatly acknowledged.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.