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CarS2-mediated cysteine catabolism drives brown fat development and thermogenesis through persulfidating EBF2

ABSTRACT: Targeting transcriptional regulatory complexes is a promising strategy to activate thermogenic fat and treat obesity. In this study, we focused on identifying critical and specific metabolic pathways enriched during brown adipocyte differentiation. By analyzing metabolomics and RNA sequencing results from precursor and mature brown and white adipocytes, we revealed cysteine catabolism pathway is a unique metabolic process that is highly increased in brown adipocyte differentiation. Then, we demonstrated cysteine persulfidation synthase CarS2 is directly induced by EBF2, mediates cysteine catabolism and triggers brown fat protein persulfidation both in vitro and in vivo. Loss of CarS2 in thermogenic fat blocks brown fat formation in both male and female mice, and CarS2 depletion in mice reduces thermogenesis and energy expenditure. More importantly, CarS2 generates cysteine persulfide, and its derivative H2S cell-autonomously induces brown adipogenesis and enhances uncoupled respiration by persulfidating EBF2. Mechanistically, persulfidated EBF2 facilitates its interaction with PPARγ or BRG1, enhancing the recruitment of the EBF2-PPARγ complex to the browning gene promoter, thus driving brown fat development and boosting thermogenic activity. Furthermore, treatment with CarS2 coenzyme PLP or H2S donor elevates brown adipocyte function and ameliorates obesity progression in mice under HFD feeding, indicating a novel metabolite-based strategy for obesity treatment.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS12234 | MetaboLights | 2026-03-24

REPOSITORIES: MetaboLights

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	Amide-L1-day-0-1.mzML	Mzml
	Amide-L1-day-0-2.mzML	Mzml
	Amide-L1-day-0-3.mzML	Mzml
	Amide-L1-day-8-1.mzML	Mzml
	Amide-L1-day-8-2.mzML	Mzml

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CarS2 mediated cysteine catabolism drives brown fat development and thermogenesis through persulfidating EBF2 [Cut & Tag]

Project description:Targeting transcriptional regulatory complex is a promising strategy to activate thermogenic fat and treat obesity. In this study, we focus on identifying critical and special metabolic pathways enriched during brown adipocyte differentiation. By analyzing metabolomics and RNA sequencing results from precursor and mature brown and white adipocytes, we revealed cysteine catabolism pathway is a unique metabolic process that is exclusively increased in the brown adipocyte differentiation. Then, we demonstrated cysteine persulfidation synthase CarS2 is directly induced by EBF2 and mediates cysteine catabolism to produce cysteine persulfide and triggers brown fat protein persulfidation in vitro and in vivo. Loss of CarS2 in thermogenic fat blocks brown and beige fat formation and reduced thermogenesis and energy expenditure in mice. More importantly, CarS2 generates cysteine persulfide and its derivative H2S cell autonomously induces brown adipogenesis and enhances uncoupled respiration by persulfidating EBF2. Mechanistically, the persulfidated EBF2 facilitates its interaction with PPARγ and enhanced the recruitment of the EBF2-PPARγ complex on browning gene promoter, thus driving brown fat development and boosting thermogenic function. Furthermore, the treatment of CarS2 coenzyme PLP or H2S donor elevates brown adipocyte function and ameliorates obesity progression in mice under HFD feeding, indicating a novel metabolite-based strategy for the obesity treatment.

2026-03-20 | GSE245346 | GEO

CarS2 mediated cysteine catabolism drives brown fat development and thermogenesis through persulfidating EBF2 [BAC and L1 differ]

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CarS2 mediated cysteine catabolism drives brown fat development and thermogenesis through persulfidating EBF2 [AKO and wt Acute cold]

2026-03-20 | GSE242242 | GEO

Cars2-Mediated Cysteine Catabolism Drives Brown Fat Development and Thermogenesis Through Persulfidating EBF2.

Project description:Targeting transcriptional regulatory complexes represents a promising strategy for activating thermogenic fat and treating obesity. In this study, we focused on identifying critical, specific metabolic pathways enriched during brown adipocyte differentiation. Through analysis of metabolomics and RNA sequencing data from precursor and mature brown and white adipocytes, we revealed that the cysteine catabolism pathway constitutes a unique metabolic process that is significantly upregulated during brown adipocyte differentiation. We further demonstrated that the cysteine persulfidation synthase Cars2, which is directly induced by EBF2, mediates cysteine catabolism and triggers brown fat protein persulfidation both in vitro and in vivo. Loss of Cars2 in thermogenic fat blocks brown fat formation, resulting in mice exhibiting reduced thermogenesis and energy expenditure. More importantly, Cars2 generates cysteine persulfide and its derivative H<sub>2</sub>S cell-autonomously induces brown adipogenesis and enhances uncoupled respiration through persulfidation of EBF2. Mechanistically, persulfidated EBF2 facilitates its interaction with PPARγ or BRG1, enhancing recruitment of the EBF2-PPARγ complex to browning gene promoters, thereby driving brown fat development and boosting thermogenic activity. Furthermore, treatment with the Cars2 coenzyme PLP or an H<sub>2</sub>S donor enhances brown adipocyte function and alleviates obesity progression in mice fed a high-fat diet, indicating a novel metabolite-based strategy for obesity treatment.

2026-03-24 | MTBLS12237 | MetaboLights

LncRNAs expression profiling in adipose tissues and during brown adipocyte differentiation

Project description:Brown and beige fats generate heat via uncoupled respiration to defend against cold, mechanistically, through the action of a network of transcription factors and cofactors. Here we globally profiled long noncoding RNAs (lncRNAs) gene expression during thermogenic adipocyte formation and identified Brown fat lncRNA 1 (Blnc1) as a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function by forming a feedforward regulatory loop with EBF2 to drive adipogenesis toward thermogenic phenotype. LncRNAs expression were measured in BAT and WAT from mice injected saline/CL and during brown adipocyte differentiation with two replicates using Arraystar Mouse LncRNA microarray V2.0

2015-02-28 | E-GEOD-57643 | biostudies-arrayexpress

NFIA Controls the Brown Fat Gene Program by Co-Localizing with PPARgamma at Cell-Type-Specific Enhancers (RNA)

Project description:Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a novel transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the adipogenic master regulator, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA is a key transcriptional regulator of brown fat and exerts its effects by co-localizing with PPARγ at cell-type-specific enhancers.

2017-08-14 | GSE83762 | GEO

EPAC1 enhances energy expenditure by selectively inducing brown and beige adipose tissue growth

Project description:Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure (EE) and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show by phosphoproteomics that cAMP activates distinct signaling pathways in brown progenitors, with the cAMP-EPAC1 axis enhancing proliferation and differentiation of thermogenic but not white adipocytes. Further analysis revealed that a specific subpopulation of preadipocytes that are PDGFRα-positive express EPAC1. In vivo, pharmacological activation of EPAC1 enhances BAT growth and browning of white fat, leading to increased EE and reduced diet-induced adiposity. In contrast, mice lacking EPAC1 in PDGFRα-positive preadipocytes show the opposite phenotype. Importantly, EPAC1 activation enhances proliferation and differentiation of human brown adipocytes and human brown fat organoids. Interestingly, a coding variant in EPAC1 that positively correlates with BMI abolishes norepinephrine-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and EE to combat metabolic diseases.

2023-11-11 | PXD046709 | Pride

Vector and Brown fat lncRNA 1 (Blnc1) expressing differentiated brown adipocytes

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. Brown adipocytes expressing vector or brown fat lncRNA 1 (blnc1) were differentiated for 6 days and harvested for RNA isolation and microarray using Affymetrix Mouse MG-430 PM Strip arrays. Two replicated samples were included in this study.

2015-02-28 | E-GEOD-55551 | biostudies-arrayexpress

Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice

Project description:Brown adipose tissue (BAT) is a thermogenic organ that dissipates stored energy as heat to maintain body temperature in infants and small mammals. This process may also provide protection from development of diet-induced obesity. We found that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, while potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibited reduced expression of BAT-related genes in peripheral white adipose tissue and accumulated significantly more fat than wild-type controls when fed a high fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and suggest that a decrease in peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice.

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Scramble and Brown fat lncRNA 1 knockdown (shBlnc1) expressing differentiated brown adipocyte

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 mitochondrial function. Brown adipocytes expressing Scramble or brown fat lncRNA 1 knockdown (shBlnc1) were differentiated for 6 days and harvested for RNA isolation and microarray using Affymetrix Mouse MG-430 PM Strip arrays. Two replicated samples were included in this study.

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