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

ABSTRACT: 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.

ORGANISM(S): Mus Musculus

SUBMITTER: Huali Shen

PROVIDER: PXD073900 | iProX | Mon Feb 02 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared to white adipose tissue (WAT), PVAT and BAT from C57BL/6 mice fed a high fat diet for 13 weeks had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80, CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b+/CD11c+ macrophages in BAT (1.0%) in comparison to WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from thermal and inflammatory stress. 8-week-old male C57BL6/J mice were fed a normal (ND) or high fat diet (HFD) (Research Diets 12451, 45 kcal% fat) for 13 weeks. Mice were then euthanized and four different adipose depots were harvested for RNA analysis: perivascular fat from the lesser curvature of the aortic arch (PVAT), interscapular brown adipose (BAT), inguinal adipose tissue (SAT), and epididymal adipose tissue (VAT). 250 ng total RNA pooled from two mice was used for cDNA synthesis; 3 biological replicates per tissue and diet were performed for a total of 24 hybridizations.

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

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