Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice

Abstract

ABSTRACT Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups – ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.