SnRNA-seq of Beiging Inguinal Adipose Tissue from UCP1-KO and WT mice under cold-stress and mice treated with Beta-Blocker and mild cold exposure.
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ABSTRACT:
PROVIDER: PRJNA730278 | ENA |
REPOSITORIES: ENA
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Project description:Atlas of UCP1-KO Beiging inguinal adipose tissue and tissue in which beta adrenergic signaling is blocked provides further insight into UCP1-independent mechanisms of beiging.
2021-05-17 | GSE174497 | 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: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
Project description:Abstract
Brown and brite adipocytes are the key cells performing uncoupling protein 1 (UCP1) dependent non-shivering thermogenesis (NST) induced by cold exposure. Several lipid species are associated to NST in brown and white adipose tissue. Studies investigating the association of the lipid profile with NST rely on the analysis of whole organ homogenates or on the differentiation of pre-adipocytes in vitro. These approaches have so far not addressed the heterogeneity of white adipose tissue. Aim of this study was to characterize the lipid composition of white adipose tissue on a region-specific level in an in vivo context.
We applied MALDI mass spectrometry imaging (MALDI-MSI) in combination with immunohistochemistry and high-resolution mass spectrometry on sections of inguinal white adipose tissue of 129S6/SvEvTac and C57BL6/N-UCP1 knockout and wildtype mice acclimatized to cold to identify lipids specific to areas of UCP1 expression.
Based on the analysis of cold exposed 129S6/SvEvTac mice we identified cardiolipins (CL) and diacylglycerols (DG) species to be specific for areas expressing UCP1 and triacylglycerols (TG) to be the main lipid class characteristic for UCP1 negative regions within inguinal white adipose tissue. Investigation of C57BL6/N-UCP1 knockout and wildtype mice housed at either room temperature or acclimatized to cold, demonstrated that CL content in white adipose tissue is increased upon cold stimulation, independent of UCP1.
We introduce a MALDI-MSI based approach to identify lipids associated to thermogenic adipocytes in adipose tissues demonstrating a clear regional cold dependent upregulation of CL independent of UCP1.
2021-04-07 | MSV000087164 | MassIVE
Project description:Single cell level analysis of transcriptional circuits regulating UCP1-indepednent theremogensis through Lgr6 in inguinal Adipose tissue. We previously identified an increase in Lgr6 gene expression in the beige adipocyte population of UCP1-KO mice and hypothesized its involvement in UCP1-independent thermogensis. Consistent with our previous data the scATAC-seq data reveals that chromatin accessibility at the Lgr6 loci is significantly higher in Ucp1- KO beige adipocytes as compared to WT and the promter is also more accessible in Ucp1- KO beige adipocytes. Other DNA-binding motifs involved in UCP-1 indepedent thermogensis were also analyzed and found to be upregulated in the KO model.
2021-05-15 | GSE174456 | 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
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:Sympathetic activation during cold exposure increases adipocyte thermogenesis via the expression of mitochondrial protein uncoupling protein 1 (UCP1)1. The propensity of adipocytes to express UCP1 is under a critical influence of the adipose microenvironment and varies between sexes and among various fat depots2-7. Here, we report that cold-induced adipocyte UCP1 expression in a female mouse subcutaneous white adipose tissue (scWAT) is regulated by mammary gland ductal epithelial cells in the adipose niche. Single-cell RNA-sequencing (scRNA-seq) shows that glandular luminal epithelium subtypes express transcripts that encode secretory factors in controlling adipocyte UCP1 expression under cold conditions. We term luminal epithelium secretory factors as “mammokines”. Using whole-tissue immunofluorescence 3D visualization, we reveal previously undescribed sympathetic nerve-ductal points of contact. We show sympathetic nerve-activated mammary ducts limit adipocyte UCP1 expression via lipocalin 2. Both in vivo and ex vivo ablation of mammary ductal epithelium enhances cold-induced scWAT adipocyte thermogenic gene program. Since the mammary duct network extends throughout most scWATs in female mice, females show markedly less scWAT UCP1 expression, fat oxidation, energy expenditure, and subcutaneous fat mass loss compared to male mice, implicating sex-specific roles of mammokines in adipose thermogenesis. These results show a previously uncharacterized role of sympathetic nerve-activated glandular epithelium in adipocyte UCP1 expression and suggest an evolutionary function of mammary duct luminal cells in defending glandular adiposity during cold exposure. Overall, our findings highlight mammary gland epithelium as a highly active metabolic cell type and implicate a broader role of mammokines in controlling female adipose metabolism, mammary gland physiology, and systemic energy homeostasis.
2023-05-01 | GSE231394 | GEO
Project description:Obesity causes insulin resistance, and PPARγ ligands like rosiglitazone (rosi) are insulin-sensitizing, yet mechanisms remain unclear. High fat diet (HFD) induced obesity has major effects on visceral epididymal adipose tissue (eWAT) of C57BL/6 (B6) mice, and here we report altered activity of gene regulatory elements with changes in PPARγ genome-wide occupancy. Treatment with rosi restored insulin sensitivity, yet surprisingly had little effect on eWAT, leading us to consider the subcutaneous inguinal fat (iWAT). In this depot, rosi markedly induced molecular signatures of brown fat including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ (129) mice showed this degree of iWAT browning even in the absence of rosi. Remarkably, the 129 Ucp1 locus had increased PPARγ binding and gene expression that was preserved in B6x129 F1 intercross iWAT, with imbalance favoring the 129-derived alleles showing a cis-acting genetic difference. Thus, B6 mice have a genetic defect in Ucp1 expression. However, imbalanced expression favoring 129 over B6 was nearly lost when Ucp1 was activated by rosi, or by iWAT browning in cold-exposed or young mice. These results provide a novel framework for understanding how environmental influences like drugs can rescue genetically determined disease phenotypes by affecting the epigenome.
2017-02-27 | GSE92606 | GEO
Project description:Obesity causes insulin resistance, and PPARγ ligands like rosiglitazone (rosi) are insulin-sensitizing, yet mechanisms remain unclear. High fat diet (HFD) induced obesity has major effects on visceral epididymal adipose tissue (eWAT) of C57BL/6 (B6) mice, and here we report altered activity of gene regulatory elements with changes in PPARγ genome-wide occupancy. Treatment with rosi restored insulin sensitivity, yet surprisingly had little effect on eWAT, leading us to consider the subcutaneous inguinal fat (iWAT). In this depot, rosi markedly induced molecular signatures of brown fat including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ (129) mice showed this degree of iWAT browning even in the absence of rosi. Remarkably, the 129 Ucp1 locus had increased PPARγ binding and gene expression that was preserved in B6x129 F1 intercross iWAT, with imbalance favoring the 129-derived alleles showing a cis-acting genetic difference. Thus, B6 mice have a genetic defect in Ucp1 expression. However, imbalanced expression favoring 129 over B6 was nearly lost when Ucp1 was activated by rosi, or by iWAT browning in cold-exposed or young mice. These results provide a novel framework for understanding how environmental influences like drugs can rescue genetically determined disease phenotypes by affecting the epigenome.
2017-02-27 | GSE91067 | GEO