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De Novo Reconstruction of Transcriptome Identified Long Non-Coding RNA Regulator of Aging-Related Brown Adipose Tissue Whitening in Rabbits.

ABSTRACT: Brown adipose tissues (BATs) convert to a "white-like" phenotype with age, which is also known as "aging-related BAT whitening (ARBW)". Emerging evidence suggested that long non-coding RNAs (lncRNAs) were widely involved in adipose biology. Rabbit is an ideal model for studying the dynamics of ARBW. In this study, we performed histological analysis and strand-specific RNA-sequencing (ssRNA-seq) of rabbit interscapular adipose tissues (iATs). Our data indicated that the rabbit iATs underwent the ARBW from 0 days to 2 years and a total of 2281 novel lncRNAs were identified in the iATs. The classical rabbit BATs showed low lncRNA transcriptional complexity compared to white adipose tissues (WATs). A total of 631 differentially expressed lncRNAs (DELs) were identified in four stages. The signal pathways of purine metabolism, Wnt signaling pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway, cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (cGMP-PKG) signaling pathway and lipid and atherosclerosis were significantly enriched by the DELs with unique expression patterns. A novel lncRNA that was highly expressed in the iATs of aged rabbits was validated to impair brown adipocyte differentiation in vitro. Our study provided a comprehensive catalog of lncRNAs involved in ARBW in rabbits, which facilitates a better understanding of adipose biology.

SUBMITTER: Du K

PROVIDER: S-EPMC8614855 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveBrown adipose tissue (BAT) thermogenesis offers the potential to improve metabolic health in mice and humans. However, humans predominantly live under thermoneutral conditions, leading to BAT whitening, a reduction in BAT mitochondrial content and metabolic activity. Recent studies have established mitophagy as a major driver of mitochondrial degradation in the whitening of thermogenic brite/beige adipocytes, yet the pathways mediating mitochondrial breakdown in whitening of classical BAT remain largely elusive. The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy belonging to the MiT family of transcription factors, is the only member of this family that is upregulated during whitening, pointing toward a role of TFEB in whitening-associated mitochondrial breakdown.MethodsWe generated brown adipocyte-specific TFEB knockout mice, and induced BAT whitening by thermoneutral housing. We characterized gene and protein expression patterns, BAT metabolic activity, systemic metabolism, and mitochondrial localization using in vivo and in vitro approaches.ResultsUnder low thermogenic activation conditions, deletion of TFEB preserves mitochondrial mass independently of mitochondriogenesis in BAT and primary brown adipocytes. However, this does not translate into elevated thermogenic capacity or protection from diet-induced obesity. Autophagosomal/lysosomal marker levels are altered in TFEB-deficient BAT and primary adipocytes, and lysosomal markers co-localize and co-purify with mitochondria in TFEB-deficient BAT, indicating trapping of mitochondria in late stages of mitophagy.ConclusionWe identify TFEB as a driver of BAT whitening, mediating mitochondrial degradation via the autophagosomal and lysosomal machinery. This study provides proof of concept that interfering with the mitochondrial degradation machinery can increase mitochondrial mass in classical BAT under human-relevant conditions. However, it must be considered that interfering with autophagy may result in accumulation of non-functional mitochondria. Future studies targeting earlier steps of mitophagy or target recognition are therefore warranted.

Dataset Information

De Novo Reconstruction of Transcriptome Identified Long Non-Coding RNA Regulator of Aging-Related Brown Adipose Tissue Whitening in Rabbits.

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