Exercise Attenuates Obesity-Related Cognitive and Sleep-Circadian Dysfunctions by Attenuating Neuroinflammation via JAK/STAT in Sex and Age Specific Manner

Genetic obesity is an escalating health challenge with profound consequences for brain function, yet the mechanisms linking metabolic dysfunction to disrupted brain aging remain poorly understood. Although sphingolipid dysmetabolism is strongly associated with the obesity–neuronal axis, its mechanistic basis has not been fully explored. To address this gap, our study identifies a loss-of-function mutation in sphingosine kinase 2 ( Sk2 ), the Drosophila ortholog of human sphingosine kinase 2 (SPHK2), as a key driver of obesity-associated neural dysfunction and evaluates the ability of exercise to mitigate these effects. We demonstrate that Sk2-driven obesity results in cognitive decline characterized by impaired memory, lipid dysregulation, chronic neuroinflammation, and disrupted sleep–circadian rhythms in a sex- and tissue-specific manner. Importantly, we show that exercise acts as a robust therapeutic intervention, reversing memory deficits, restoring brain lipid homeostasis, and normalizing sleep–circadian activity. Mechanistically, our findings identify the JAK/STAT signaling pathway as a critical mediator of exercise-induced neuroprotection, linking reduced neuroinflammation with enhanced cognitive resilience. Notably, we uncover distinct sex- and age-dependent differences in both obesity-induced impairments and responsiveness to exercise, indicating divergent regulatory mechanisms between males and females. Together, these findings establish a novel link between genetic obesity, brain dysfunction, and lifestyle-based interventions, highlighting exercise as a promising non-pharmacological strategy to counteract obesity-associated neurocognitive and circadian disturbances.