Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

ABSTRACT: Coenzyme Q is an essential component of mitochondrial function and required for thermogenic activity in brown adipose tissues (BAT). BAT CoQ deficiency (50-75%) by genetic or pharmacological means does not interfere with basal or maximal mitochondrial respiration in brown adipocytes but increases mitochondrial oxidants and induces UPRmt, ISR, and repression of UCP1 expression. ATF4, the master regulator of ISR, is required for UCP1 suppression in BAT CoQ deficiency. In animals, BAT CoQ deficiency causes cold intolerance but activates compensatory thermogenic mechanisms in BAT and other tissues via greatly induced BAT FGF21 expression resulting in paradoxically upregulated whole-body respiration rates and protection from obesity at room temperature and thermoneutrality. BAT-specific loss of either ATF4 or FGF21 abolishes these metabolic benefits demonstrating a central role for CoQ in the modulation of whole-body energy expenditure and thus for the etiology of primary and secondary CoQ deficiencies.

ORGANISM(S): Mus musculus

PROVIDER: GSE165940 | GEO | 2022/02/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Histone Deacetylase 3 Prepares Brown Adipose Tissue For Acute Thermogenic Challenge [RNA-Seq]

Project description:Brown adipose tissue (BAT) is a thermogenic organ that requires Uncoupling Protein 1 (UCP1) to dissipate chemical energy as heat, to defend core body temperature against hypothermia, and counteract obesity and metabolic diseases1. However, the transcriptional mechanism ensuring BAT thermogenic capacity for survival prior to environmental cold is unknown. Here we show histone deacetylase 3 (HDAC3) is a required transcriptional regulator of BAT enhancers to ensure thermogenic aptitude and survival. Mice with genetic ablation of HDAC3 become severely hypothermic and fail to survive acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes. Remarkably, although HDAC3 canonically functions as a transcriptional corepressor2, HDAC3 functions as a coactivator of the estrogen-related receptor _ (ERR_) in BAT, and loss of HDAC3 leads to robust global down-regulation of ERR±-driven enhancers. HDAC3 coactivation of ERR_ is mediated through deacetylation of PGC-1_ and is required for basal transcription of Ucp1, OXPHOS, and Pgc-1_. Thus, HDAC3 uniquely primes Ucp1 and thermogenic gene transcription to ensure immediate BAT-driven thermogenesis upon acute exposure to dangerously cold temperatures.

2017-06-14 | GSE83927 | GEO

Histone Deacetylase 3 Prepares Brown Adipose Tissue For Acute Thermogenic Challenge [ChIP-Seq, GRO-Seq]

2017-06-14 | GSE83926 | GEO

GCN2 is required to maintain core body temperature in mice during acute cold.

Project description:Non-shivering thermogenesis in the brown adipose tissue (BAT) of rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. Therefore, it is critical to identify signaling pathways which aid in nutrient delivery within this thermogenic tissue.To understand the contribution of the integrated stress response (ISR) in directing adaptive thermogenesis, we examined the role of the kinase activity of general control nonderepressible 2 (GCN2) within the BAT during acute cold exposure. We hypothesized that under hypothermic conditions, GCN2 maintains thermogenesis via ISR gene targets such as fibroblast growth factor 21 (FGF21), that triggers thermogenic uncoupling in BAT. In alignment with our hypothesis, both female and male mice either lacking GCN2 or administered a small molecule inhibitor of GCN2 were profoundly intolerant to acute cold stress. However, while GCN2 deletion in male mice impeded liver-derived FGF21 expression, it did not affect FGF21 levels in females, suggesting an alternative role for GCN2 in the maintenance of thermogenesis. Within the BAT, acute cold exposure increased ISR target genes and thermogenic genes regardless of GCN2 status and sex. RNA sequencing in BAT during cold exposure revealed a gene signature that identified actomyosin mechanics and transmembrane transport as the top two processes requiring GCN2. The top gene signature included cytoskeletal and class II myosin heavy chain genes critical for maximal thermogenesis during cold stress. The second gene signature included amino acid transporters which corresponded with higher circulating amino acids. In conclusion, we identify a novel role for GCN2 activation during acute cold exposure to facilitate mechanosensitive cell signaling and use of amino acids for adaptive thermogenesis.

2023-11-21 | GSE234972 | GEO

Elucidating the role of UCP1 and FGF21 for metabolic homeostasis in the cold

Project description:Global RNA sequencing analysis of the hypothalamus, BAT, inguinal WAT and muscle of long-term cold exposed WT, FGF21 KO, UCP1 KO and UCP1/FGF21 double KO mice

2017-08-16 | GSE99412 | GEO

Impact of UCP1 and FGF21 for the development of diet-induced obesity at standard housing temperatures

Project description:Global RNA sequencing analysis of brown fat (BAT), inguinal white fat (iWAT), liver and muscle (quadriceps) of high-fat diet fed WT, FGF21 KO, UCP1 KO and UCP1/FGF21 double KO mice.

2019-11-05 | GSE122167 | GEO

Human brown and white preadipocyes clonal dynamics predict themorgenic potential and function

Project description:Brown adipose tissue (BAT) holds therapeutic potential for obesity and metabolic syndrome via increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generation of brown and white preadipocyte clones from human neck fat and characterized their adipogenic differentiation and thermogenic function. Combining a UCP1 reporter system and gene expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of mature adipocytes. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes by CRISPRs markedly abolished the high level of UCP1 in mature brown adipocytes. Finally, we showed the ability to prospectively isolate adipose progenitors with great thermogenic potential. These data provide new insights into the cellular heterogeneity in human fat and offer clinically relevant gene targets that mark thermogenically competent preadipocytes. Highly adipogenic clonal white and brown cell lines

2015-06-15 | E-GEOD-68544 | biostudies-arrayexpress

Actomyosin-mediated tension orchestrates uncoupled respiration in adipose tissues

Project description:The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein-1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Adrenergic signaling is viewed as a key regulator of thermogenesis and UCP1-expression in BAT, while also operating as a potent contractile stimulator in muscle. The muscle-like gene expression patterns of UCP1+ adipocytes have previously been utilized as tissue specific markers, but have not been attributed with any functional role. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. We show that activation of actomyosin mechanics are critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Additionally, actomyosin-mediated elasticity regulates mechanosensitive transcriptional co-activators, YAP/TAZ, that facilitate the thermogenic capacity of adipocytes. These unappreciated signaling and mechanical mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.

2018-03-01 | GSE109829 | GEO

SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1  

Project description:Objective: Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial deacetylase.   Methods: We carried out physiological, molecular and proteomic analyses of BAT from wild-type and Sirt3KO mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the β3-adrenergic agonist, CL316,243 (1mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetyaltion lysine sites on UCP1 function. Cardiac punctures were collected for Proteomic analysis of Acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS.   Results: Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII.  

2019-04-18 | PXD013056 | Pride

Proteome imbalance of mitochondrial electron transport chain in brown adipocytes leads to metabolic benefits

Project description:Adaptive thermogenesis of brown adipose tissue (BAT) is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that mice with a BAT-specific Liver kinase b1 deletion (Lkb1BKO mice) exhibited impaired mitochondrial respiration and thermogenesis in BAT, but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to impaired mitochondrial respiration in BAT of Lkb1BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the tradeoff between BAT thermogenesis and systemic metabolism at both room temperature and thermoneutrality. Collectively, our data demonstrates that ETC proteome imbalance in BAT regulates systemic metabolism independently of BAT thermogenic capacity.

2018-07-12 | PXD008599 | Pride

Bulk RNAseq of Mus musculus Protein Kinase D1 (Prkd1) knock-out adipose tissue in response to thermoneutral and cold exposure stress

Project description:Brown adipose tissue (BAT) has in recent times been rediscovered in adult humans, and together with work from preclinical models, shown to have the potential of providing a variety of positive metabolic benefits. These include improved insulin sensitivity and reduced susceptibility to obesity and its various co-morbidities. As such, its continued study could offer insights to therapeutically modulate this tissue to improve metabolic health. It has been reported that adipose-specific deletion of the gene for protein kinase D1 (Prkd1) enhances mitochondrial respiration and improves whole-body glucose homeostasis. We sought to determine whether these effects were mediated specifically through brown adipocytes using a Prkd1 brown adipose tissue (BAT) Ucp1-Cre-specific knockout mouse model, Prkd1BKO. We unexpectedly observed that upon both cold exposure and beta-3-AR agonist administration, Prkd1 loss in BAT did not alter canonical thermogenic gene expression or adipocyte morphology. We took an unbiased approach to assess whether other signaling pathways were altered. RNAs from cold-exposed control and Prkd1BKO were subjected to RNA-Seq analysis. These studies revealed that myogenic gene expression is altered in Prkd1BKO BAT after both acute (8 hr) and extended (4 day) cold exposure. Given that brown adipocytes and skeletal myocytes share a common precursor cell lineage expressing myogenic factor 5 (Myf5), these data suggest that loss of Prkd1 in BAT may alter the biology of preadipocytes in this depot. The data presented herein clarify the role of Prkd1 in BAT thermogenesis and present new avenues for the further study of Prkd1 function in BAT.

2023-09-01 | E-MTAB-12170 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data