Comprehensive transcriptional profiling and mouse phenotyping reveals dispensable role for adipose tissue selective long noncoding RNA Gm15551.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200656 | GEO | 2022/05/12
REPOSITORIES: GEO
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Project description:Cold and nutrient-activated brown adipose tissue (BAT) is capable of increasing systemic energy expenditure via the uncoupled respiration and secretion of endocrine factors, thereby protecting mice against diet-induced obesity and improving insulin response and glucose tolerance in men. Long non-coding RNAs (lncRNAs) have recently been identified as fine-tuning regulators of cellular function. While certain lncRNAs have been functionally characterised in adipose tissue, their overall contribution in the activation of BAT remains elusive. We identified lncRNAs correlating to interscapular brown adipose tissue (iBAT) function in a high fat diet (HFD) and cold stressed mice. We focused on Gm15551, which has an adipose tissue specific expression profile, is highly upregulated during adipogenesis, and downregulated by β-adrenergic activation in mature adipocytes. Although we performed comprehensive transcriptional and adipocyte physiology profiling in vitro and in vivo, we could not detect an effect of gain or loss of function of Gm15551.
| S-EPMC9149892 | biostudies-literature
Project description:Comprehensive transcriptional profiling and mouse phenotyping reveals dispensable role for adipose tissue selective long noncoding RNA Gm15551.
| PRJNA825721 | ENA
Project description:ObjectiveLong noncoding RNAs (lncRNAs) are emerging as powerful regulators of adipocyte differentiation and gene expression. However, their significance in adipose tissue metabolism and physiology has not been demonstrated in vivo. We previously identified Blnc1 as a conserved lncRNA regulator of brown and beige adipocyte differentiation. In this study, we investigated the physiological role of Blnc1 in thermogenesis, adipose remodeling and systemic metabolism.MethodsWe generated fat-specific Blnc1 transgenic and conditional knockout mouse strains and investigated how adipocyte Blnc1 levels are causally linked to key aspects of metabolic health following diet-induced obesity. We performed studies using cultured adipocytes to establish cell-autonomous role of Blnc1 in regulating adipocyte gene programs.ResultsBlnc1 is highly induced in both brown and white fats from obese mice. Fat-specific inactivation of Blnc1 impairs cold-induced thermogenesis and browning and exacerbates obesity-associated brown fat whitening, adipose tissue inflammation and fibrosis, leading to more severe insulin resistance and hepatic steatosis. On the contrary, transgenic expression of Blnc1 in adipose tissue elicits the opposite and beneficial metabolic effects, supporting a critical role of Blnc1 in driving adipose adaptation and homeostatic remodeling during obesity. Mechanistically, Blnc1 cell-autonomously attenuates proinflammatory cytokine signaling and promotes fuel storage in adipocytes through its protein partner Zbtb7b.ConclusionsThis study illustrates a surprisingly pleiotropic and dominant role of lncRNA in driving adaptive adipose tissue remodeling and preserving metabolic health.
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Project description:NEAT1 is one of the most studied lncRNAs, in part because its silencing in mice causes defects in mammary gland development and corpus luteum formation and protects them from skin cancer development. Moreover, depleting NEAT1 in established cancer cell lines reduces growth and sensitizes cells to DNA damaging agents. However, NEAT1 produces two isoforms and because the short isoform, NEAT1_1, completely overlaps the 5' part of the long NEAT1_2 isoform; the respective contributions of each of the isoforms to these phenotypes has remained unclear. Whereas NEAT1_1 is highly expressed in most tissues, NEAT1_2 is the central architectural component of paraspeckles, which are nuclear bodies that assemble in specific tissues and cells exposed to various forms of stress. Using dual RNA-FISH to detect both NEAT1_1 outside of the paraspeckles and NEAT1_2/NEAT1 inside this nuclear body, we report herein that NEAT1_1 levels are dynamically regulated during the cell cycle and targeted for degradation by the nuclear RNA exosome. Unexpectedly, however, cancer cells engineered to lack NEAT1_1, but not NEAT1_2, do not exhibit cell cycle defects. Moreover, Neat1_1-specific knockout mice do not exhibit the phenotypes observed in Neat1-deficient mice. We propose that NEAT1 functions are mainly, if not exclusively, attributable to NEAT1_2 and, by extension, to paraspeckles.
| S-EPMC6859857 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-to-date lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.
| S-EPMC7397864 | biostudies-literature
Project description:Enhancing brown fat activity and promoting white fat browning are attractive therapeutic strategies for treating obesity and associated metabolic disorders. To provide a comprehensive picture of the gene regulatory network in these processes, we conducted a series of transcriptome studies by RNA sequencing (RNA-seq) and quantified the mRNA and long noncoding RNA (lncRNA) changes during white fat browning (chronic cold exposure, beta-adrenergic agonist treatment, and intense exercise) and brown fat activation or inactivation (acute cold exposure or thermoneutrality, respectively). mRNA-lncRNA coexpression networks revealed dynamically regulated lncRNAs to be largely embedded in nutrient and energy metabolism pathways. We identified a brown adipose tissue-enriched lncRNA, lncBATE10, that was governed by the cAMP-cAMP response element-binding protein (Creb) axis and required for a full brown fat differentiation and white fat browning program. Mechanistically, lncBATE10 can decoy Celf1 from Pgc1α, thereby protecting Pgc1α mRNA from repression by Celf1. Together, these studies provide a comprehensive data framework to interrogate the transcriptomic changes accompanying energy homeostasis transition in adipose tissue.
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Project description:BackgroundPersistent symptoms after initial COVID-19 infection are common and are frequently referred to by the umbrella terms "post-COVID syndrome" and "long COVID". The sheer number of affected patients pose an increasing challenge to healthcare systems worldwide. To date, our understanding of the pathophysiology of the post-COVID syndrome remains poor and the extent to which persistent cardiopulmonary abnormalities contribute to the symptom complex is unclear. We sought to determine the presence and impact of cardiopulmonary sequelae after COVID-19 in longitudinal assessment.MethodsWe report on 71 patients who underwent comprehensive, longitudinal testing in regular intervals for up to 12 months after their initial COVID-19 diagnosis. Testing included pulmonary function testing, cardiopulmonary exercise testing, dedicated left and right heart echocardiography, lung ultrasonography, and cardiac MRI.ResultsOur results demonstrate that subjective quality of life after COVID-19 (EQ-5D visual acuity scale, VAS, 67.4 for patients treated as outpatient, 79.2 for patients admitted to the general floor, 71.8 for patients treated in an ICU) is not related to the severity of the initial infection. Maximal exercise capacity is also reduced (VO2max 79% predicted, SD ± 19%); however, this is driven in large parts by patients who had initially required ICU-level of care. The degree of objective reduction in exertion did not correlate with quality of life scores. Pulmonary function testing revealed mild and persistent reduction in DLCO over the first 12 months without significant restrictive or obstructive lung disease. Left and right heart function was intact with good RV function and intact RV/PA coupling, imaging findings suggestive of myocarditis were uncommon (7% of patients).ConclusionA reduction in exercise capacity after COVID-19 is common, but is most prominent in patients previously treated in the ICU and more likely related to deconditioning or fatigue than to cardiopulmonary impairment. Subjective quality of life scores are independent of the severity of initial infection and do not correlate with objective measures of cardiopulmonary function. In our cohort, persistent cardiopulmonary impairment after COVID-19 was uncommon. The post-COVID syndrome is unlikely to be the result of cardiopulmonary sequalae and may reflect a post-ICU syndrome in some. Trial registration Registered on clinicaltrials.gov (NCT04442789), Date: June 23, 2020.
| S-EPMC9491263 | biostudies-literature
Project description:Adipose tissue (AT) macrophages (ATMs) contribute to obesity-induced inflammation and metabolic dysfunction, but also play critical roles in maintaining tissue homeostasis. ATMs catabolize lipid in a lysosomal-dependent manner required for the maintenance of AT; deficiency in lysosomal acid lipase (Lipa), the enzyme required for lysosome lipid catabolism, leads to AT atrophy and severe hepatic steatosis, phenotypes rescued by macrophage-specific expression of Lipa Autophagy delivers cellular products, including lipid droplets, to lysosomes. Given that obesity increases autophagy in AT and contributes to lipid catabolism in other cells, it was proposed that autophagy delivers lipid to lysosomes in ATMs and is required for AT homeostasis. We found that obesity does increase autophagy in ATMs. However, genetic or pharmacological inhibition of autophagy does not alter the lipid balance of ATMs in vitro or in vivo. In contrast to the deficiency of lysosomal lipid hydrolysis, the ablation of autophagy in macrophages does not lead to AT atrophy or alter metabolic phenotypes in lean or obese animals. Although the lysosomal catabolism of lipid is necessary for normal ATM function and AT homeostasis, delivery of lipid to lysosomes is not autophagy dependent and strongly suggests the existence of another lipid delivery pathway critical to lysosome triglyceride hydrolysis in ATMs.
| S-EPMC4806658 | biostudies-literature
Project description:The expression profile of long noncoding RNA (lncRNA) in human epicardial adipose tissue (EAT) has not been widely studied. In the present study, we performed RNA sequencing to analyze the expression profiles of lncRNA and mRNA in EAT in coronary artery disease (CAD) patients with and without heart failure (HF). Our results showed RNA sequencing disclosed 35673 mRNA and 11087 lncRNA corresponding to 15554 genes in EAT in total, while 30 differentially expressed lncRNAs (17 upregulated and 13 downregulated) and 278 differentially expressed mRNAs (129 upregulated and 149 downregulated) were discriminated between CAD patients with and without HF (P<0.05; fold change>2); lncRNA ENST00000610659 drew specific attention for it was the top upregulated lncRNA with highest fold change and corresponded to UNC93B1 gene, which was proved to be related to HF and encoded UNC93B1 protein regulating toll-like receptor signaling, and both of them significantly increased in HF patients in qRT-PCR validation; the top significant upregulated enriched GO terms and KEGG pathway analysis were regulation of lymphocyte activation (GO:0051249) and T cell receptor signaling pathway (hsa04660), respectively. The current findings support the fact that EAT lncRNAs are involved in the inflammatory response leading to the development of HF.
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Project description:Brown adipocytes store metabolic energy as triglycerides (TGs) in lipid droplets (LDs). Fatty acids released from brown adipocyte LDs by lipolysis are thought to activate and fuel UCP1-mediated thermogenesis. Here, we test this hypothesis by preventing fatty acid storage in murine brown adipocytes through brown adipose tissue (BAT)-specific deletions of the TG synthesis enzymes DGAT1 and DGAT2 (BA-DGAT KO). Despite the absence of TGs in brown adipocytes, BAT is functional, and BA-DGAT-KO mice maintain euthermia during acute or chronic cold exposure. As apparent adaptations to the lack of TG, brown adipocytes of BA-DGAT-KO mice appear to use circulating glucose and fatty acids, and stored glycogen, to fuel thermogenesis. Moreover, BA-DGAT-KO mice are resistant to diet-induced glucose intolerance, likely because of increased glucose disposal by BAT. We conclude that TGs in BAT are dispensable for its contribution to cold-induced thermogenesis, at least when other fuel sources are available.
| S-EPMC7696656 | biostudies-literature