VTADA Neurons Mediate Sleep Deprivation-Induced Brown Adipose Metabolism via Brain-Brown Adipose Axis

Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the mechanisms remain poorly understood. Using acute and chronic sleep deprivation (SD) mouse models, we found that dopaminergic (DA) neurons, particularly in theventral tegmental area (VTA), are activated during SD. Spatial micro-proteomics revealed distinctprotein expression profiles in VTA DA neurons: acute SD altered synaptic function, while chronic SDupregulated pathways linked to fatty acid oxidation, thermogenesis, and energy metabolism.Chronic SD increased basal metabolism (elevated oxygen consumption, respiratory entropy) andreduced brown adipose tissue (BAT) mass, accompanied by lipid droplet redistribution. Neuraltracing identified direct synaptic connections between VTA DA neurons and BAT. Targetedmanipulation of Eci1 in VTA DA neurons recapitulated SD-induced metabolic changes, includingreduced sleep, increased energy expenditure, and altered adipocyte morphology. These findingsestablish a brain-adipose axis through which VTA DA neurons requlate lipid metabolism andthermogenesis during sleep deprivation.