An ER-anchored peptide C4orf3/ALN controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1118717 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29247562_1.fastq.gz | Fastqsanger.gz | |||
| SRR29247562_2.fastq.gz | Fastqsanger.gz | |||
| SRR29247563_1.fastq.gz | Fastqsanger.gz | |||
| SRR29247563_2.fastq.gz | Fastqsanger.gz | |||
| SRR29247564_1.fastq.gz | Fastqsanger.gz |
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Project description:Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca2+ cycling via SERCA2b in subcutaneous adipose tissues; however, the molecular underpinnings of this process remain elusive. Here, we report that an ER-membrane anchored peptide C4orf3 (also known as anotherregulin, ALN) uncouples its Ca2+ transport from ATP-hydrolysis by interacting via the cytoplasmic domain, rendering the SERCA2b-C4orf3/ALN complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2-dependent Ca2+ transport, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. In turn, overexpression of C4orf3/ALN promotes Ca2+ cycling thermogenesis in the microsomal compartment. Of note, genetic depletion of C4orf3 led to compensatory activation of mitochondrial thermogenesis via UCP1 following cold challenge. We found that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study uncovers the molecular mechanisms and the physiological role of UCP1-independent Ca2+ cycling thermogenesis in adipose tissue. This RNA-seq data set showed that double knockdown (DKO) of UCP1 and C4orf3/ALN increased lipid catabolism in adipose tissue.
2025-03-28 | GSE268770 | GEO
Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.
2024-01-10 | PXD047841 | Pride
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
Project description:Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
2022-02-17 | PXD024717 | Pride
Project description:We tested if minor changes in maternal non-shivering thermogenesis during pregnancy can severely alter the phenotype of the offspring already in the next generation. Therefore, male offspring of dams lacking the uncoupling protein 1 (UCP1-KO) in the thermogenic brown adipose tissue were analysed. Genome-wide expression profiling identified several alterations in the hepatic transcriptomic landscape, demonstrating that even minor differences in the demand for maternal thermogenesis profoundly and permanently alter hepatic gene activity in the adult offspring. Liver gene expression data of offspring from WT and UCP1-KO dams.
2020-11-09 | GSE145143 | GEO
Project description:Uncoupling protein 1 (UCP1) is thought to be a major regulator of whole-body energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss of function model has recently been shown to have destructive effects on the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as an allosteric site on UCP1 that elevates protein activity upon covalent modification. Here we examine the physiological importance of this site through the generation of a UCP1 cysteine-253 null mouse (UCP1 C253A), the first genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, instead we find that lack of cysteine-253 results in substantial immune cell infiltration and inflammatory pathology in adipose tissues of male, but not female mice. Together, our results establish the UCP1 cysteine-253 activation site as a regulator of acute thermogenesis and sex-dependent adipose tissue inflammation.
2021-12-15 | PXD029270 | Pride
Project description:Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue (BAT) to produce heat through sympathetic nervous system (SNS)- and -adrenergic receptors (ARs). The AR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood. Here we described that specific ablation of cAMP production in brown adipocytes led to reduced lipolysis, mitochondrial biogenesis, uncoupling protein 1 (Ucp1) expression, and consequently defective adaptive thermogenesis. Elevated cAMP signaling by sympathetic activation inhibited Salt-inducible kinase 2 (Sik2) through protein kinase A (PKA)-mediated phosphorylation in brown adipose tissue. Inhibition of SIKs enhanced Ucp1 expression in differentiated brown adipocytes and Sik2 knockout mice exhibited enhanced adaptive thermogenesis at thermoneutrality in an Ucp1-dependent manner. Taken together, our data indicate that suppressing Sik2 by PKA-mediated phosphorylation is a requisite for SNS-induced Ucp1 expression and adaptive thermogenesis in BAT, and targeting Sik2 may present a novel therapeutic strategy to ramp up BAT thermogenic activity in humans.
2018-07-12 | PXD009262 | Pride
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:Differentiation of brown adipocytes is a crucial process for adaptive thermogenesis, which is stimulated by various factors. We found robust browning of inguinal white adipose tissue in UCP1/ApoE-DKO mice, but not in ApoE-KO mice, under high-fat diet condition. We used microarray to determine the genes specifically regulated in the browning white adipose tissue in UCP1/ApoE-DKO mice.
2018-10-01 | GSE95273 | GEO