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Elevated 1-deoxysphingolipids in adipose tissue promote inflammation

ABSTRACT: Chronic adipose tissue inflammation is a hallmark of numerous metabolic disorders, yet its initial triggers remain elusive. Here, we discover that excessive accumulation of toxic 1-deoxysphingolipid (DoxSL), a non-canonical sphingolipid species, in adipose tissue leads to the local release of pro-inflammatory cytokines. Mechanistically, DoxSL is sequestered in lipid droplets within adipose tissue to mitigate cytotoxicity under physiological conditions, but its levels are significantly elevated in states such as obesity and aging. A targeted increase in DoxSL triggers adipose tissue inflammation and macrophage infiltration via activation of the NF-κB pathway. Notably, reducing DoxSL levels through pharmacological treatment attenuates inflammation in obese mice. These findings uncover a previously unknown metabolic mechanism and emphasize a critical role of lipids in driving adipose tissue inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE283339 | GEO | 2025/12/31

REPOSITORIES: GEO

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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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Elevated 1-deoxysphingolipids in adipose tissue promote inflammation

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