Exercise attenuates obesity-related cognitive and sleep-circadian dysfunctions by attenuating neuroinflammation via JAK/STAT in sex and age specific manner.

Abstract

Obesity including genetic obesity accelerates age-related cognitive decline and disrupts circadian regulation, increasing the risk of neurodegenerative disorders. These effects are mediated in part by metabolic dysregulation, neuroinflammation, and altered sleep-circadian cycles, yet the molecular and lifestyle factors that modify obesity-associated brain dysfunction remain poorly defined. We investigated whether exercise mitigates metabolic, cognitive, and circadian dysfunction associated with genetic obesity, and whether exercise responses differ by sex and age. Using Drosophila melanogaster (fruit fly), we compared Canton-S (CS) controls with flies carrying a loss-of-function mutation in sphingosine kinase 2 (Sk2), a conserved regulator of sphingolipid metabolism linked to obesity. Male and female flies were assessed at 3 and 6 weeks of age under exercised and non-exercised conditions. Outcomes included brain and peripheral lipid accumulation, synaptic marker expression, neuroinflammatory and apoptotic gene expression, sleep-circadian architecture, and olfactory aversive learning. Flies with Sk2-associated obesity exhibited increased lipid accumulation, synaptic dysregulation, neuroinflammation, sleep fragmentation, and cognitive impairment, with severity increasing with age. Endurance exercise significantly attenuated these abnormalities, but responses were sex- and age-dependent. Exercise reduced brain lipid burden and synapsin expression predominantly in males, whereas females showed greater suppression of inflammatory and apoptotic signaling. Sleep continuity and circadian stability improved markedly with exercise in females, while cognitive performance was rescued in both sexes, with stronger effects at younger ages. Endurance exercise mitigates obesity-associated metabolic, inflammatory, circadian, and cognitive dysfunction in a genetic Drosophila model, with distinct sex- and age-specific patterns of benefit. These findings highlight exercise as a powerful, non-pharmacological modifier of obesity-related brain aging/inflammation and underscore the importance of considering biological sex and intervention timing when designing strategies to promote healthy aging.