Aging Induced Syntaxin 4 Deficiency Mediates Brown Adipose Tissue Pyroptosis and Thermogenic Dysfunction
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ABSTRACT:
PROVIDER: PRJNA956945 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24205812_1.fastq.gz | Fastqsanger.gz | |||
| SRR24205812_2.fastq.gz | Fastqsanger.gz | |||
| SRR24205813_1.fastq.gz | Fastqsanger.gz | |||
| SRR24205813_2.fastq.gz | Fastqsanger.gz | |||
| SRR24205814_1.fastq.gz | Fastqsanger.gz |
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Project description:Aging, chronic high fat diet feeding and housing at thermoneutrality induces brown adipose tissue (BAT) involution, a process characterized by reduction of BAT mass and function with increased lipid droplet size. Syntaxin 4 (STX4) was identified as a healthy longevity gene, in contrast endogenous STX4 protein levels in BAT declined in aged mice resulting in pyroptotic activation of caspase 1/4 signaling pathway. Single nuclei RNA sequencing of aged mice identified a specific brown adipocyte population of UCP1low cells that were Stx4 low and pyroptotic. Similarly, UCP1Stx4KO mice led to age-dependent loss of brown adipose tissue mass concomitant with increased pyroptosis whereas restoring STX4 expression protected against pyroptosis and decline in thermogenic activity. Moreover, STX4 deficiency reduced oxidative phosphorylation, glucose uptake and glycolysis leading to reduced ATP levels, a known signal for pyroptosis. All these data demonstrate a new model of rapid brown adipocyte involution and that physiologic aging and BAT involution results from pyroptotic signaling activation.
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Project description:Sustained responses to transient stimuli are important for animals to survive and reproduce in their environment. However, the mechanisms that underlie altered responses to temporary shifts in abiotic factors, such as temperature, remain poorly understood. Here, we find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which are critical for an improved thermogenic response to secondary cold encounter. Primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis program even after cessation of the original stimulus, which protects from subsequent exposures. By combining single-nucleus RNA sequencing, spatial transcriptomics, and immunofluorescence imaging, we discover that this lipogenic response is carried out by a distinct subpopulation of brown adipocytes that is localized along the perimeter of classical Ucp1high brown adipocytes. The protective effect of the lipogenic program is associated with the production of acyl carnitines, and supplementation of acyl carnitines recapitulates improved secondary cold responses even in the absence of lipogenesis. Overall, our data highlight the importance of heterogenous brown adipocyte populations for “thermogenic memory” in the setting of repeated cold exposure, which may have implications for therapeutic efforts leveraging short-term thermogenesis to counteract the hypercaloric state of obesity.
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Project description:Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutical strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity observed in Sox4-MKO mice increases their susceptibility to diet-induced obesity. Overexpression of SOX4 enhances BAT thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates transcription of EBF2 which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2 providing valuable insights into BAT development and thermogenic function maintenance.
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Project description:Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutical strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity observed in Sox4-MKO mice increases their susceptibility to diet-induced obesity. Overexpression of SOX4 enhances BAT thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates transcription of EBF2 which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2 providing valuable insights into BAT development and thermogenic function maintenance.
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Project description:Blnc1 is a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype. We used microarrays to elucidate the role of Blnc1 on brown adipocyte differentiation and the induction of the thermogenic gene program.
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