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RNA-sequence analysis of JMJD1A target genes in subcutanous white adipose tissue.

ABSTRACT: Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE236733 | GEO | 2024/03/12

REPOSITORIES: GEO

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ATAC-sequence analysis of immortalized subcutanous white adipose tissue cells.

Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

2024-03-12 | GSE236724 | GEO

RNA-sequence analysis of immortalized, differentiated preadipocytes derived from inguinal subcutaneous white adipose tissue.

Project description:In acute cold stress in mammals, JMJD1A, an H3K9 demethylase, up-regulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals also have another mechanism to cope with long-term cold stress by inducing the browning of subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation independent acute Ucp1 induction in BAT and demethylation dependent chronic Ucp1 expression in beige-scWAT provide complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namlely β-adrenergic receptor and PPARγ activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis.

2018-02-16 | GSE107900 | GEO

Genome-wide analysis of JMJD1A and PPARγ binding in immortalized, differentiated preadipocytes derived from inguinal subcutaneous white adipose tissue.

2018-02-16 | GSE107899 | 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

PKA-dependent Phosphorylation of A Histone Demethylase Drives Higher Order Chromatin Structures by Association with SWI/SNF Chromatin Remodeler

Project description:The current studies show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate expression of the b1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1. Phosphorylation of JMJD1A increases its interaction with the SWI/SNF nucleosome remodeling complex and DNA-bound PPARg. This complex conferred b-adrenergic-induced JMJD1A recruitment to target sites throughout the genome. Phospho-JMJD1A also facilitated long-range chromatin looping to recruit PPARg-bound distal-enhancers, SWI/SNF, and RNA polymerase close to the Adrb1 locus to activate transcription. Mutation of the PKA-phosphorylation site on JMJD1A abolished interactions with SWI/SNF without affecting demethylase activity suggesting the two functions are independent of each other. Our results show that JMJD1A demethylase is also a signal-sensing scaffold that regulates cAMP-responsive transcription via interactions with SWI/SNF and hormone stimulated higher-order chromatin conformational changes. There are 3 samples analyzed. No duplication from each sample. Isoproterenol stimulation at 0hr is used as the relative to fold change in manuscript.

2015-04-15 | E-GEOD-58936 | biostudies-arrayexpress

Lrpprc deficiency in brown adipocytes diminishes cold-induced thermogenesis but improves systemic metabolism

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

Fam172a deletion in brown adipose tissue protects against HFD-induced obesity by activating the BDH1-BHB pathway

Project description:Family with sequence similarity 172 member A (FAM172A) protein acts as a key physiological repressor of brown adipose tissue (BAT) activity that plays a key role in energy metabolism. Its expression in BAT is suppressed by cold and other adrenergic stimulators. Mechanistically, FAM172A inhibits BAT activity and thermogenesis, in part, by binding to 3-hydroxybutyrate dehydrogenase 1 (BDH1), which subsequently affects the levels of beta-hydroxybutyrate (BHB), a ketone body metabolite closely involved in adipose mitochondrial biogenesis.

2023-08-29 | GSE241732 | GEO

PKA-dependent Phosphorylation of A Histone Demethylase Drives Higher Order Chromatin Structures by Association with SWI/SNF Chromatin Remodeler

2015-04-15 | GSE58936 | GEO

RNA sequencing of WT and ERRαγAd-/- brown adipose tissue treated with CL316,243

Project description:Adrenergic stimulation of brown adipose tissue (BAT) activates thermogenesis, by uncoupling oxidative phosphorylation and enabling high rates of substrate oxidation. Moreover, adrenergic stimulation signals to the nucleus, inducing gene expression changes that increase BAT thermogenic and oxidative capacity. The purpose of this study was to determine the role of two orphan nuclear receptors, ERRα and ERRγ, in adipose tissue function in response to adrenergic stimulation. Here we identify ERRα and ERRγ as collectively critical effectors of the adrenergic induced transcriptional program in BAT. Mice lacking adipose ERRs (ERRαγAd-/-) have diminished oxidative and thermogenic capacity, and become rapidly hypothermic when exposed to cold. Notably, the ability of the β3-adrenergic agonist CL316,243 to expand BAT oxidative and thermogenic capacity, increase energy expenditure, promote weight loss, and improve glucose tolerance is lost in ERRαγAd-/-. At the transcriptional level, RNA sequencing experiments show that the bulk of the response of BAT to CL316,243 (>80% of CL316,243-induced genes) relies on ERRs. These findings establish ERRα and ERRγ as essential BAT regulators that act coordinately to relay adrenergic signals and expand the capacity for thermogenesis and energy expenditure.

2018-03-19 | GSE104285 | GEO

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance

Project description:Brown adipose tissue (BAT), a crucial heat-generating organ, regulate whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we sought whether BAT inflammation regulates systematic metabolism and thermogenesis. By using mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), we evaluated the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results describe that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS-STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT; uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

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