CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA986130 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24985600_1.fastq.gz | Fastqsanger.gz | |||
| SRR24985600_2.fastq.gz | Fastqsanger.gz | |||
| SRR24985593_1.fastq.gz | Fastqsanger.gz | |||
| SRR24985593_2.fastq.gz | Fastqsanger.gz | |||
| SRR24985594_1.fastq.gz | Fastqsanger.gz |
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Project description:Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1β, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a previously unknown brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.
2023-08-23 | GSE235476 | GEO
Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
2021-07-19 | GSE178366 | GEO
Project description:Insufficient mitochondrial quantity in brown adipose tissue (BAT) causes defective thermogenesis and positive energy balance, which is coupled with the development of obesity. Whether disturbance of mitochondrial quality affects BAT function remains unknown. Here, we describe that the brown adipocyte-specific Leucine-rich PPR motif-containing protein knockout mice (LrpprcBKO) exhibited mitochondrial electron transport chain (ETC) proteome imbalance and a complete loss of the -adrenergic-stimulated thermogenesis at room temperature (RT), due to specific reduction of mtDNA-encoded genes. However, the LrpprcBKO mice were lean at normal chow and were protected against high-fat-diet-induced metabolic abnormalities, such as obesity, insulin resistance, adipose inflammation, hepatic steatosis, and hypertriglyceridemia. The beige adipocytes in inguinal white adipose tissue were expanded in LrpprcBKO mice at RT, but not at thermoneutrality. However, BAT thermogenic defects and metabolic benefits were present in LrpprcBKO mice regardless of ambient temperatures. Collectively, our results reveal that a thermogenesis-incapable BAT with mitochondrial ETC proteome imbalance can improve systemic metabolism, suggesting BAT’s contributions to thermoregulation and systemic metabolism can be uncoupled.
2021-10-07 | PXD008798 | Pride
Project description:Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.
2024-11-13 | PXD057026 | Pride
Project description:Brown adipocytes are unique in that they expend energy and produce heat to maintain euthermia through expression of uncoupling protein-1 (UCP1). Given their propensity to stimulate weight loss and promote resistance to obesity, they are a compelling interventional target for obesity-related disorders. Here, we tested whether an optogenetic approach could be used to activate UCP1-dependent thermogenesis in brown adipocytes. We generated brown adipocytes expressing a bacterial-derived photoactivatable adenylyl cyclase (bPAC) that, upon blue light stimulation, increases UCP1 expression, fuel uptake and thermogenesis. This unique system allows for precise, chemical free, temporal control of UCP1-dependent thermogenesis, which can aid in our understanding of brown adipocyte biology and development of therapies that target obesity-related disorders.
| S-EPMC10139976 | biostudies-literature
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
2024-05-09 | GSE244457 | GEO
Project description:Mammals have two types of thermogenic adipocytes: brown adipocytes and beige adipocytes. Thermogenic adipocytes express high levels of uncoupling protein 1 (UCP1) to dissipates energy in the form of heat by uncoupling the mitochondrial proton gradient from mitochondrial respiration. There is much evidence that UCP1 is the center of BAT thermogenesis and systemic energy homeostasis. Recently, UCP1 independent thermogenic pathway identified in thermogenic adipocytes. Importantly, the thermogenic pathways are different in brown and beige adipocytes. Ca2+-ATPase 2b calcium cycling mechanism is selective to beige adipocytes. It remains unknown how the multiple thermogenic mechanisms are coordinately regulated. The discovery of UCP1-independent thermogenic mechanisms potential offer new opportunities for improving obesity and type 2 diabetes particularly in groups such as elderly and obese populations who do not possess UCP1 positive adipocytes.
| S-EPMC7399049 | biostudies-literature
Project description:The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.
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Project description: Not available
| S-EPMC10471955 | biostudies-literature
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
2024-05-09 | GSE245509 | GEO