Abstract
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16, and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-CoA and lipid metabolism. Concordantly, cytoplasmic acetyl-CoA levels and global histone H3 acetylation were decreased. Further, activating histone marks (H3K27ac and H3K9ac) in promoters/enhancers of brown marker genes showed reduced acetylation status. Taken together, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. Thereby, we mechanistically connect the NAA pathway to the epigenomic regulation of gene expression, modulating the phenotype of brown adipocytes.
Highlights
in an unregulated control locus (Ins) contrast to white adipocytes that store energy as triglycerides in uni-locular lipid droplets, brown adipocytes exhibit multi-locular lipid droplets, are rich in mitochondria, and evolved to dissipate energy as heat in endothermal, placental animals[1,2,3]
We showed that increased expression of Nat8l and Aspa enhances the phenotype of brown adipocytes[25]
Using HPLC-MS/MS we showed a ~100-fold increase of intracellular NAA concentrations in immortalized brown adipocytes (iBACs) differentiated with NAA (Fig. 1a)
Summary
In contrast to white adipocytes that store energy as triglycerides in uni-locular lipid droplets, brown adipocytes exhibit multi-locular lipid droplets, are rich in mitochondria, and evolved to dissipate energy as heat in endothermal, placental animals[1,2,3]. The importance of an intact NAA pathway is apparent as deleterious mutations in the human ASPA gene lead to Canavan disease, a fatal neurological disorder caused by a myelination defect in the central nervous system[16,17]. Studies with rats exhibited that dietary-supplemented NAA is bioavailable[30], but neither evokes systemic toxicity nor adverse effects on the CNS30,31 as NAA does not cross the blood brain barrier[30,32] Together, these data suggest a prominent physiological role of NAA in peripheral tissues. Our work connects the NAA pathway to the regulation of the brown adipocyte transcriptome and with that its phenotype
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