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Transcriptional determinants of lipid mobilization in human adipocytes [CUT&Tag]

ABSTRACT: Defects in white adipose tissue lipolysis drive multiple aspects of cardiometabolic disease but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as: i) transcription factors, ii) histone variant chaperones, and iii) mRNA processing proteins. Based on its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on ZNF189, which encodes the Zinc Finger Protein 189. Using mass-spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of Phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2 and overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247817 | GEO | 2023/11/24

REPOSITORIES: GEO

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Transcriptional determinants of lipid mobilization in human adipocytes

Project description:Defects in white adipose tissue lipolysis drive multiple aspects of cardiometabolic disease but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as: i) transcription factors, ii) histone variant chaperones, and iii) mRNA processing proteins. Based on its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on ZNF189, which encodes the Zinc Finger Protein 189. Using mass-spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of Phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2 and overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization. [Manuscript Abstract]

2024-01-17 | PXD046964 | Pride

Transcriptional determinants of lipid mobilization in human adipocytes [ATAC-seq]

2023-11-24 | GSE247815 | GEO

Transcriptional determinants of lipid mobilization in human adipocytes [ChIP-seq]

2023-11-24 | GSE247814 | GEO

Transcriptional determinants of lipid mobilization in human adipocytes [Microarray]

2023-11-24 | GSE247813 | GEO

Altered adipose lipid mobilization predicts long-term weight gain and impaired glucose metabolism

Project description:Factors predicting body weight gain and associated disturbed glucose metabolism remain to be established. Here we assessed the role of subcutaneous adipocyte lipid mobilization (lipolysis) in spontaneous long-term (>10 years) body weight changes. In two independent clinical cohorts we found that low stimulated lipolysis at baseline correlated inversely with body mass index changes over time. Disturbed lipolysis gave odds ratios of ≥4.6 for weight gain and ≥3.2 for development of insulin resistance and impaired fasting glucose/type 2 diabetes. Baseline adipose mRNA expression of a set of established lipolysis-regulating genes was lower in weight gainers.

2018-04-13 | GSE113080 | GEO

Transcriptional co-factor TBLR1 controls lipid mobilization in white adipose tissue

Project description:Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional co-factor transducin beta-like-related (TBLR) 1 blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and when placed on a high fat diet show aggravated adiposity, glucose intolerance and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFA). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes may thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders. We used microarrays to identify global gene expression in 3T3-L1 adipocytes lacking TBLR1 and compared gene expression to control shRNA treated cells in both basal and isoproterenol stimulated states. We analyzed 12 RNA samples extracted from 3T3-L1 adipocytes that were treated with either control or TBLR1 specific shRNAs and with or without 10 ÂµM isoproterenol for 3 hrs. Three replicates of each condition.

2013-04-01 | E-GEOD-43658 | biostudies-arrayexpress

Transcriptional co-factor TBLR1 controls lipid mobilization in white adipose tissue

2013-04-01 | GSE43658 | GEO

A sunflower WRKY transcription factor stimulates the mobilization of seed-stored reserves during germination and post-germination growth

Project description:Germinating oilseeds convert stored lipids into sugars and thereafter in metabolic energy that is used in seedling growth and establishment. During germination, the induced lipolysis linked to the glyoxylate pathway and gluconeogenesis produces sucrose, which is then transported to the embryo and driven through catabolic routes. Herein, we report that the sunflower transcription factor HaWRKY10 regulates carbon partitioning by reducing carbohydrate catabolism and increasing lipolysis and gluconeogenesis. HaWRKY10 was regulated by abscisic acid and gibberellins in the embryo leaves and highly expressed during sunflower seed germination and seedling growth, concomitantly with lipid mobilization. Sunflower leaf discs overexpressing HaWRKY10 showed repressed the expression of genes related to sucrose cleavage and glycolysis compared to controls. Moreover, HaWRKY10 constitutive expression in Arabidopsis seeds produced higher decrease in lipid reserves, whereas starch and sucrose were more preserved compared to wild type. Gene transcripts abundance and enzyme activities involved in stored lipid mobilization and gluconeogenesis increased more in transgenic than in wild type seeds 36 hours after imbibition whereas the negative regulator of lipid mobilization, ABI4, was repressed. Altogether, the results point out a functional parallelism between tissues and plant species, and reveal HaWRKY10 as a positive regulator of storage reserve mobilization in sunflower.

2016-06-04 | GSE80675 | GEO

Wnt/Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

Project description:The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its involvement in lipid mobilization has remained unclear. Here, we report that canonical Wnt/Wg signaling reduces lipid accumulation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila. This reduction occurs through promoting lipolysis while concurrently repressing lipogenesis and fatty acid β-oxidation. Leveraging RNA-sequencing and CUT&RUN assays, we have identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased triglyceride accumulation in lipid droplets, increased lipolysis, and reduced fatty acid β-oxidation. These changes lead to elevated free fatty acids and reduced triglyceride accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes triglyceride accumulation in both larval and adult stages. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Collectively, our findings suggest that Wnt signaling-induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid β-oxidation processes.

2024-06-18 | GSE264356 | GEO

Endotoxin stimulates lipolysis in bovine adipocytes

Project description:As cows progress from pregnancy to lactation, the adipose tissues (AT) undergo adaptations characterized by the mobilization of free fatty acids (FFA) through lipolysis to address energy deficiencies. Typically, in clinically healthy cows, the intensity of lipolysis decreases during lactation. However, when the release of FFA surpasses tissue requirements, it leads to the accumulation of lipid-derived products, heightening the susceptibility of cows to metabolic and infectious diseases. A second factor correlated to disease incidence in dairy cows is the presence of bacterial endotoxins in blood. The last is implicated in AT lipolysis and dysfunction in mammals. However, the mechanisms by which endotoxin activates lipolysis and affects the formation of lipid derived products in bovine adipocyte remains unknown. We hypothesize that endotoxin triggers AT dysfunction by increasing the synthesis and release of lipid-derived products with proinflammatory potential. Preadipocytes were obtained from subcutaneous AT of multiparous Holstein cows (n=9). Adipogenesis was induced for 7 d and cells were incubated with endotoxin [lipopolysaccharide 1µg/mL (LPS)] for up to 7 h. Beta-adrenergic receptor agonist isoproterenol (ISO; 1 µM) was used as an activator of canonical lipolysis. The antilipolytic effect of insulin was evaluated alone or in combination with LPS. Lipolysis was evaluated by the release of glycerol in the media. RNA from adipocytes was sequenced in Illumina NextSeqData, and Differential Expressed Genes (DEG) identified. Enrichment and network analyses were performed in Ingenuity Pathways (IPA). Our findings provide evidence supporting the higher abundance of lipid-derived products with proinflammatory activity and dysfunction related to inflammatory activation.

2024-05-20 | GSE267141 | GEO

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