TMEM135 Links Peroxisomes to the Regulation of Brown Fat Mitochondrial Fission and Energy Homeostasis
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Thermo Q Exactive Plus
ORGANISM(S): Mus <mouse, Genus> (ncbitaxon:10088)
SUBMITTER: 
Irfan J. Lodhi
PROVIDER: MSV000090693 | MassIVE | Thu Nov 10 14:03:00 GMT 2022
SECONDARY ACCESSION(S): PXD038088
REPOSITORIES: MassIVE
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Project description:Increases in organismal energy expenditure, as during cold exposure or exercise training, can improve metabolic health. This process is dependent also on brown adipose tissue (BAT) thermogenesis in mice and humans. Understanding and harnessing the molecular circuits activating BAT function is thus of great interest to devise novel approaches to counteract obesity and type 2 diabetes (T2D). In contrast to protein-coding genes, the role of long noncoding RNAs (lncRNAs) during BAT differentiation and function remains poorly understood. To address this, we performed RNA-Seq and identified the maternal allele-specific (imprinted) lncRNA H19 increased upon cold-mediated BAT activation and decreased upon chronic diet-induced obesity (DIO) BAT dysfunction. An inverse correlation of H19 expression with body-mass indices (BMI) was observed in a cohort of >160 lean and obese humans. H19 silencing impaired adipogenesis and oxidative metabolism in brown but not white adipocytes, while H19 gain-of-function increased nutrient oxidation and mitochondrial respiration, thus supporting a BAT-regulatory role for H19. In vivo H19 overexpression protected against DIO, improved insulin sensitivity and rescued DIO-mediated defects in energy expenditure in conjunction with improved mitochondrial biogenesis. In contrast, BAT-selective H19 loss decreased energy dissipation and sensitized towards high fat diet-induced body weight gains. When investigating other parent-of-origin specific, monoallelically expressed genes, we strikingly observed that paternally expressed genes (PEGs) were largely absent from BAT and coordinately downregulated during brown adipogenesis, whilst the same gene set was robustly expressed in white fat stores, a phenomenon not observed for maternally expressed genes (MEGs). Using H19 loss- and gain-of-function in primary adipocytes, we demonstrate that H19 acts as ‘PEG gatekeeper’ in brown, not white adipocytes, potentially due to recruitment of PEG-inactivating H19-MBD1 complexes in mature brown adipocytes. The exclusive PEG expression in white adipose tissuer could underly the observed susceptibility of mice exhibiting high PEG abundances towards DIO-evoked weight gain. Collectively, we here define novel roles for the imprinted lncRNA H19 in brown adipocyte differentiation and function in vitro, control of energy expenditure in vivo and repression of paternal allele-specific gene expression in BAT. This has far-reaching implications for our understanding of how monoallelical gene expression affects metabolic eustasis in both rodent models and, potentially, human patients.
2018-06-26 | GSE116226 | GEO
Project description:Increases in organismal energy expenditure, as during cold exposure or exercise training, can improve metabolic health. This process is dependent also on brown adipose tissue (BAT) thermogenesis in mice and humans. Understanding and harnessing the molecular circuits activating BAT function is thus of great interest to devise novel approaches to counteract obesity and type 2 diabetes (T2D). In contrast to protein-coding genes, the role of long noncoding RNAs (lncRNAs) during BAT differentiation and function remains poorly understood. To address this, we performed RNA-Seq and identified the maternal allele-specific (imprinted) lncRNA H19 increased upon cold-mediated BAT activation and decreased upon chronic diet-induced obesity (DIO) BAT dysfunction. An inverse correlation of H19 expression with body-mass indices (BMI) was observed in a cohort of >160 lean and obese humans. H19 silencing impaired adipogenesis and oxidative metabolism in brown but not white adipocytes, while H19 gain-of-function increased nutrient oxidation and mitochondrial respiration, thus supporting a BAT-regulatory role for H19. In vivo H19 overexpression protected against DIO, improved insulin sensitivity and rescued DIO-mediated defects in energy expenditure in conjunction with improved mitochondrial biogenesis. In contrast, BAT-selective H19 loss decreased energy dissipation and sensitized towards high fat diet-induced body weight gains. When investigating other parent-of-origin specific, monoallelically expressed genes, we strikingly observed that paternally expressed genes (PEGs) were largely absent from BAT and coordinately downregulated during brown adipogenesis, whilst the same gene set was robustly expressed in white fat stores, a phenomenon not observed for maternally expressed genes (MEGs). Using H19 loss- and gain-of-function in primary adipocytes, we demonstrate that H19 acts as ‘PEG gatekeeper’ in brown, not white adipocytes, potentially due to recruitment of PEG-inactivating H19-MBD1 complexes in mature brown adipocytes. The exclusive PEG expression in white adipose tissuer could underly the observed susceptibility of mice exhibiting high PEG abundances towards DIO-evoked weight gain. Collectively, we here define novel roles for the imprinted lncRNA H19 in brown adipocyte differentiation and function in vitro, control of energy expenditure in vivo and repression of paternal allele-specific gene expression in BAT. This has far-reaching implications for our understanding of how monoallelical gene expression affects metabolic eustasis in both rodent models and, potentially, human patients.
2018-06-26 | GSE116225 | GEO
Project description:The mitochondrial calcium uniporter has been proposed to coordinate the organelle’s energetics with cytosolic calcium signaling. Previous studies have shown that the uniporter current is extremely high in mitochondria from brown adipose tissue (BAT), yet the contribution of the uniporter to BAT physiology in vivo is not known. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice are born in Mendelian ratios on a C57BL6/J genetic background, without any overt phenotypes. Although uniporter based calcium uptake is selectively ablated in BAT mitochondria, these mice are able to defend their body temperature in response to cold challenge and exhibit a normal body weight trajectory on a high fat diet. BAT transcriptional profiles at baseline and following cold-challenge are intact and not impacted by loss of Mcu. Unexpectedly, we found that cold powerfully activates the ATF4-dependent integrated stress response in BAT, and increases both circulating FGF21 and GDF15 levels, raising the hypothesis that the integrated stress response partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis, and unexpectedly, uncovers a striking activation of the integrated stress response of BAT to cold challenge.
2019-04-30 | GSE119964 | GEO
Project description:Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.
2024-02-15 | PXD043992 | Pride
Project description:Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.
2024-02-15 | PXD044020 | Pride
Project description:Brown adipose tissue (BAT) is a promising weapon to combat obesity and metabolic disease. BAT is thermogenic and consumes substantial amounts of glucose and fatty acids as fuel for thermogenesis and energy expenditure. To study BAT function in large human longitudinal cohorts, safe and precise detection methodologies are needed. Although regarded a gold standard, the foray of PET-CT into BAT research and clinical applications is limited by its high ionizing radiation doses. Here, we show that brown adipocytes release exosomes in blood plasma which can be utilized to assess BAT activity. In this study, we investigated circulating protein biomarkers that can accurately and reliably reflect BAT activation triggered by cold exposure, capsinoids ingestion and thyroid hormone excess in humans.
2022-06-09 | PXD023909 | 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:Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold identify FAM210A as a cold-inducible mitochondrial inner membrane protein. Adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice lethal hyperthermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state, non-thermogenic mitochondria under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
2023-08-26 | PXD044866 | Pride
Project description:<p>Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.</p>
2022-08-12 | MTBLS4856 | MetaboLights
Project description:Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 hours) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1a along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1a prevented the protective effect of STEMCT. Remarkably, the protection of HDAC3 BAT KO mice from cold intolerance following STEMCT lasted for up to 7 days. Transcriptional activator C/EBPb was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Furthermore, analysis of C/EBPb activity revealed increased binding following STEMCT at genes, including the enhancers/promotors of UCP1 and PGC-1a. These results reveal the existence of a cold-adaptive epigenomic memory mediated by C/EBPb that is persistent and HDAC3-independent.
2024-07-05 | GSE244383 | GEO