Data-driven identification of small molecules inducing Brown Adipocyte differentiation
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ABSTRACT:
PROVIDER: PRJNA1132533 | ENA |
REPOSITORIES: ENA
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Project description:Promoting the recruitment and function of human brown adipose tissue (BAT) holds significant promise for preventing and treating obesity and related metabolic complications. While identifying genes to enhance BAT recruitment and thermogenic activation is crucial, traditional upregulation methods often lack efficiency. Small molecules, however, can effectively facilitate this process through safe and rapid mechanisms. In our study, we employed the DECCODE method, an unbiased drug-induced transcriptomics approach, to identify small molecules that facilitated cell conversion. We began by establishing a transcriptomic profile of BAT cells as our target and then assessed small molecules from the LINCS collection for their similarity to this target, thus identifying a pool of candidates. Our validation in human thermogenic adipocytes revealed that three drugs—Saxagliptin, Tolvaptan, and Targinine—already approved for other uses significantly enhance BAT recruitment and activation in a human thermogenic adipocyte cellular model.
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Project description:Attainment of a brown adipocyte cell phenotype in white adipocytes, with their abundant mitochondria and increased energy expenditure potential, is a legitimate strategy for combating obesity. The unique transcriptional regulators of the primary brown adipocyte phenotype are unknown, limiting our ability to promote brown adipogenesis over white. In the present work, we used microarray analysis strategies to study primary preadipocytes, and we made the striking discovery that brown preadipocytes demonstrate a myogenic transcriptional signature, whereas both brown and white primary preadipocytes demonstrate signatures distinct from those found in immortalized adipogenic models. We found a plausible SIRT1-related transcriptional signature during brown adipocyte differentiation that may contribute to silencing the myogenic signature. In contrast to brown preadipocytes or skeletal muscle cells, white preadipocytes express Tcf21, a transcription factor that has been shown to suppress myogenesis and nuclear receptor activity. In addition, we identified a number of developmental genes that are differentially expressed between brown and white preadipocytes and that have recently been implicated in human obesity. The interlinkage between the myocyte and the brown preadipocyte confirms the distinct origin for brown versus white adipose tissue and also represents a plausible explanation as to why brown adipocytes ultimately specialize in lipid catabolism rather than storage, much like oxidative skeletal muscle tissue. Keywords: In vitro differentiation
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Project description:Blnc1 is a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype. We used microarrays to elucidate the role of Blnc1 on brown adipocyte differentiation and mitochondrial function. Brown adipocytes expressing Scramble or brown fat lncRNA 1 knockdown (shBlnc1) were differentiated for 6 days and harvested for RNA isolation and microarray using Affymetrix Mouse MG-430 PM Strip arrays. Two replicated samples were included in this study.
2015-02-28 | E-GEOD-57540 | biostudies-arrayexpress
Project description:Blnc1 is a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype. We used microarrays to elucidate the role of Blnc1 on brown adipocyte differentiation and mitochondrial function.
2015-02-28 | GSE57540 | GEO
Project description:Mouse brown adipocyte single nucleus RNAseq with Smartseq2
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Project description:Brown adipose tissue plays a crucial role in modulating whole-body energy expenditure through the thermogenic function of its mitochondrial respiratory chain. Pharmacological interventions targeting this function hold significant therapeutic promise. Thus, gaining a comprehensive understanding of the pathophysiological regulation of brown adipose tissue is imperative for future therapeutic applications. In this study, we investigated the metabolic mechanisms underlying the regulation of mature brown adipocyte function by the mitochondrial respiratory chain. Our findings indicate that deficiency in mitochondrial complex I in mature brown adipocytes leads to lipidomic remodeling. This remodeling results in an increase in arachidonic acid content and prostaglandin E2 (PGE2) production, leading to reduced transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor alpha (PPARα) and alterations in the content of PPAR activator complexes, which consequently result in reduced brown adipocyte thermogenesis and peroxisomal gene expression in mature brown adipocyte. In summary, our study elucidates that the mitochondrial-derived arachidonic acid signal regulates brown adipocyte thermogenesis and peroxisome biogenesis by modulating the PPAR activator complex."
2024-05-03 | GSE266292 | GEO
Project description:Brown and beige fats generate heat via uncoupled respiration to defend against cold, mechanistically, through the action of a network of transcription factors and cofactors. Here we globally profiled long noncoding RNAs (lncRNAs) gene expression during thermogenic adipocyte formation and identified Brown fat lncRNA 1 (Blnc1) as a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function by forming a feedforward regulatory loop with EBF2 to drive adipogenesis toward thermogenic phenotype. LncRNAs expression were measured in BAT and WAT from mice injected saline/CL and during brown adipocyte differentiation with two replicates using Arraystar Mouse LncRNA microarray V2.0
2015-02-28 | E-GEOD-57643 | biostudies-arrayexpress
Project description:To treat obesity and its related metabolism, small molecules can be used. To investigate the role of small molecules, butein, sulfuretin, and resveratrol were treated in differentiated adipocytes to find important regulators in adipocyte biology. Each small molecules have their own charactaristics on adipocyte biology, comparison of expression profiles among three small molecules can offer new insight in adipocyte biology.
2016-01-09 | GSE76672 | GEO
Project description:Brown and beige fats generate heat via uncoupled respiration to defend against cold, mechanistically, through the action of a network of transcription factors and cofactors. Here we globally profiled long noncoding RNAs (lncRNAs) gene expression during thermogenic adipocyte formation and identified Brown fat lncRNA 1 (Blnc1) as a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function by forming a feedforward regulatory loop with EBF2 to drive adipogenesis toward thermogenic phenotype.
2015-02-28 | GSE57643 | GEO
Project description:Attainment of a brown adipocyte cell phenotype in white adipocytes, with their abundant mitochondria and increased energy expenditure potential, is a legitimate strategy for combating obesity. The unique transcriptional regulators of the primary brown adipocyte phenotype are unknown, limiting our ability to promote brown adipogenesis over white. In the present work, we used microarray analysis strategies to study primary preadipocytes, and we made the striking discovery that brown preadipocytes demonstrate a myogenic transcriptional signature, whereas both brown and white primary preadipocytes demonstrate signatures distinct from those found in immortalized adipogenic models. We found a plausible SIRT1-related transcriptional signature during brown adipocyte differentiation that may contribute to silencing the myogenic signature. In contrast to brown preadipocytes or skeletal muscle cells, white preadipocytes express Tcf21, a transcription factor that has been shown to suppress myogenesis and nuclear receptor activity. In addition, we identified a number of developmental genes that are differentially expressed between brown and white preadipocytes and that have recently been implicated in human obesity. The interlinkage between the myocyte and the brown preadipocyte confirms the distinct origin for brown versus white adipose tissue and also represents a plausible explanation as to why brown adipocytes ultimately specialize in lipid catabolism rather than storage, much like oxidative skeletal muscle tissue. Experiment Overall Design: Comparisons of white and brown pre- and mature-adiposytes
2009-04-08 | E-GEOD-7032 | biostudies-arrayexpress