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Reconstructing human Brown Fat developmental trajectory in vitro

ABSTRACT: Brown adipocytes represent a specialized type of mammalian adipocytes able to uncouple nutrients catabolism and ATP generation to dissipate energy as heat. They play an important role in mammals, allowing non-shivering thermogenesis to regulate body temperature in response to cold exposure. In humans, the brown fat tissue is dispersed in small depots found throughout the neck and trunk region. Increasing brown fat activity either with drug treatment or with cell therapy approaches are considered as potential approaches for the treatment of metabolic syndrome and obesity. The recent development of in vitro differentiation strategies relying on human pluripotent stem cells (hPSCs) offers in theory the possibility to produce unlimited amounts of BAT. A strategy efficiently applied to several tissues is to recapitulate step by step the development of the tissue of interest by exposing hPSCs to the signaling cues used during normal embryonic development. However, this strategy has proven difficult to implement for brown fat as the development of this tissue is poorly characterized. Here, we first used single cell RNA sequencing to characterize the development of interscapular brown fat in mouse. Our analysis identified a previously unrecognized population of brown adipocytes precursors characterized by expression of the transcription factor GATA6. We showed that this precursor population can be efficiently generated from hPSCs by modulating the signaling pathways identified our transcriptomic analysis in paraxial mesoderm precursors differentiated in vitro. These precursors can in turn be efficiently converted into functional brown adipocytes which can respond to adrenergic stimuli by increasing their metabolism resulting in heat production.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185518 | GEO | 2021/10/11

REPOSITORIES: GEO

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Reconstructing human Brown Fat developmental trajectory in vitro

Project description:Brown adipocytes represent a specialized type of mammalian adipocytes able to uncouple nutrients catabolism and ATP generation to dissipate energy as heat. They play an important role in mammals, allowing non-shivering thermogenesis to regulate body temperature in response to cold exposure. In humans, the brown fat tissue is dispersed in small depots found throughout the neck and trunk region. Increasing brown fat activity either with drug treatment or with cell therapy approaches are considered as potential approaches for the treatment of metabolic syndrome and obesity. The recent development of in vitro differentiation strategies relying on human pluripotent stem cells (hPSCs) offers in theory the possibility to produce unlimited amounts of BAT. A strategy efficiently applied to several tissues is to recapitulate step by step the development of the tissue of interest by exposing hPSCs to the signaling cues used during normal embryonic development. However, this strategy has proven difficult to implement for brown fat as the development of this tissue is poorly characterized. Here, we first used single cell RNA sequencing to characterize the development of interscapular brown fat in mouse. Our analysis identified a previously unrecognized population of brown adipocytes precursors characterized by expression of the transcription factor GATA6. We showed that this precursor population can be efficiently generated from hPSCs by modulating the signaling pathways identified our transcriptomic analysis in paraxial mesoderm precursors differentiated in vitro. These precursors can in turn be efficiently converted into functional brown adipocytes which can respond to adrenergic stimuli by increasing their metabolism resulting in heat production.

2022-12-01 | GSE185623 | GEO

Cold induces a -adrenergicindependent thermogenic gene program in subcutaneous adipose tissue

Project description:Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and -adrenergic signaling, but here we report that cold temperature can directly activate a thermogenic gene program in adipocytes independent of -adrenergic signaling.

2018-08-16 | E-MTAB-4526 | biostudies-arrayexpress

Expression data from mouse primary brown preadipocytes

Project description:Brown adipocytes are specialized for heat generation and energy expenditure as a defense against cold and obesity. Recent studies demonstrate that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of PRDM16. Here, we identified a brown fat-enriched miRNA cluster mir-193b-365 as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes dramatically impaired brown adipocyte adipogenesis whereas myogenic markers were significantly induced. Forced expression of miR-193b and/or miR-365 in C2C12 myoblasts blocked the entire program of myogenesis, and miR-193b induced myoblasts to differentiate into brown adipocytes. Mir-193b-365 was upregulated by PRDM16. Our results demonstrate that mir-193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis.

2011-05-02 | GSE27614 | GEO

Expression data from mouse primary brown preadipocytes

2011-05-02 | E-GEOD-27614 | biostudies-arrayexpress

Unravelling the developmental roadmap towards human brown adipose tissue

Project description:We have developed and characterised functionally and molecularly a new chemically-defined protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs) that overcomes current limitations This protocol recapitulates step-by-step the physiological developmental path of human BAT. The BAs obtained expresses brown adipocyte and thermogenic markers, are insulin sensitive, and responsive to β-adrenergic stimuli. This new protocol is scalable, enabling the study of human BAs at early stages of development.

2021-03-07 | GSE168387 | GEO

A methyltransferase EHMT1 controls brown adipose cell fate and adaptive thermogenesis through a PRDM16 complex

Project description:Brown adipose tissue (BAT) dissipates chemical energy in the form of heat, as a defense against hypothermia and obesity. Current evidence indicates that brown adipocytes arise from Myf5+-dermotomal precursors through the action of a PRDM16-C/EBP-_ transcriptional complex; however, the underlying mechanisms that determine lineage specification and maintenance of brown adipose cells remain poorly understood. Here we study the role of euchromatic histone-lysine N-methyltransferase 1 (EHMT1), a brown fat-enriched lysine methyltransferase, as an essential enzymatic component of the PRDM16 transcriptional complex and controls brown adipose cell fate. To identify targets and function of EHMT1, we performed genome-wide gene expression profiling of BAT from control mouce (Ehmt1flox/flox), Ehmt1Myf5 KO mouse (Myf5-Cre+/-; Ehmt1flox/flox) and Ehmt1adipo KO mouse (Adipo-Cre+/-; Ehmt1flox/flox). Loss of EHMT1 in Myf5+ lineage causes a near total loss of brown fat characteristics and induces muscle-selective gene program in vivo. In addition, adipose-specific deletion of EHMT1 by Adipo-Cre leads to a marked reduction of the thermogenic and fat oxidation genes.

2013-11-07 | E-MTAB-1704 | biostudies-arrayexpress

MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes

Project description:Brown adipose tissue is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs as essential regulators of brown adipocyte differentiation, but it remains unknown whether microRNAs are required for the feature maintenance of mature brown adipocytes. To address this question, we ablated Dgcr8, a key regulator of the microRNA biogenesis pathway, in mature brown as well as white adipocytes. The adipose tissue -specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat, and the mice were intolerant to cold exposure. In vitro primary brown adipocyte cultures confirmed that microRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that microRNAs are essential for the browning of subcutaneous white adipocyte both in vitro and in vivo. Using this animal model, we performed microRNA expression profiling analysis and identified a set of BAT-specific microRNAs that are up-regulated during brown adipocyte differentiation and enriched in brown fat compared to other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of microRNAs in the maintenance as well as the differentiation of brown adipocytes.

2014-08-07 | GSE60165 | GEO

Effect of sesaminol on C2C12 cells on myogenesis pathway

Project description:Adipocytes are key players in maintaining energy homeostasis and are classified into two different categories: white and brown adipocyte. While white adipocytes store energy as triacylglycerols in lipid droplets, brown adipocytes combust excess chemical energy and release in the form of heat through uncoupled respiration. This characteristic phenomenon of brown fat attracts researchers and pharmacological industries to view brown fat as one of the potential therapeutic targets for obesity and associated metabolic disease. In the current study, we investigated the effect of a small molecule, sesaminol (SML) on brown fat activity and found that SML induces thermogenic program in primary white adipocytes as well as chow diet fed mice. In particular, SML treatment to mice elevated mitochondrial complex proteins and the rate oxygen consumption in brown and white fat. Administration of SML to high fat diet (HFD) challenged mice decreased weight gain, adiposity and cholesterol levels along with an increase of brown fat gene program in brown and white fat. Mechanistically, SML repressed the myogenic gene program in C2C12 myoblasts and increased all mitochondrial marker genes as appeared in brown adipose cells. Together, our results demonstrate that SML stimulates brown adipose function and protects mice against diet induced weight gain.

2020-03-27 | GSE147599 | GEO

Transcription profiling of differentiated brown adipocytes from wild type, PGC-1 alpha knockout, or PGC-1 alpha knockout and PGC-1 beta knockdown mice to investigate the roles of PGC-1 coactivators in brown fat differentiation.

Project description:Mitochondria play an essential role in the ability of brown fat to generate heat, and the PGC-1 coactivators control several aspects of mitochondrial biogenesis. To investigate their specific roles in brown fat cells, we generated immortal preadipocyte lines from the brown adipose tissue of mice lacking PGC-1±. We could then efficiently knockdown PGC-1Î² expression by shRNA expression. Loss of PGC-1± did not alter brown fat differentiation but severely reduced the induction of thermogenic genes. Cells deficient in either PGC-1Î± or PGC-1Î² coactivators showed a small decrease in the differentiation-dependant program of mitochondrial biogenesis and respiration; however, this increase in mitochondrial number and function was totally abolished during brown fat differentiation when both PGC-1± and PGC-1 were deficient. These data show that PGC-1± is essential for brown fat thermogenesis but not brown fat differentiation, and the PGC-1 coactivators play an absolutely essential but complementary function in differentiation-induced mitochondrial biogenesis. Affymetrix microarray analysis of total RNA from wt, PGC-1± KO and PGC-1± KO; cells expressing an RNAi specific for PGC-1 knockdown was performed. Of the 461; mitochondrial genes analyzed, 181 were found to be at least 20% different between wt; and defective PGC-1± and Î² adipocytes (p < 0.05). More than 85% of these genes were downregulated in cells deficient for PGC-1alpha and PGC-1beta. Experiment Overall Design: Brown preadipocytes that were either WT, KO for PGC-1alpha, or KO for PGC-1alpha and deficient for PGC-1beta (knockdown through siRNA expression) were differentiated for seven days. RNA was made from biological replicates of the three different types of brown adipocytes (WT, KO expressing a control siRNA, KO expressing a siRNA specific for PGC-1beta knockdown).

2007-11-27 | E-GEOD-5042 | biostudies-arrayexpress

PPARg agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein

Project description:Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity. PPARγ ligands have been shown to induce the browning of white adipocytes; however, the underlying mechanisms remain unclear. Here we show that PPARγ ligands require full agonism to induce a brown fat gene program preferentially in subcutaneous white adipose. These effects require expression of PRDM16, a factor that controls the development of classical brown fat. Depletion of PRDM16 blunts the effects of the PPARγ agonist rosiglitazone on the induced brown fat gene program. Conversely, PRDM16 and rosiglitazone synergistically activate the brown fat gene program in vivo. This synergy is tightly associated with an increased accumulation of PRDM16 protein, due in large measure to an increase in the half-life of the protein in agonist treated cells. Identifying compounds that stabilize PRDM16 protein may represent a novel therapeutic pathway for the treatment of obesity and diabetes. Microarray analysis of the differentiated inguinal adipocytes expressing sh-scr or sh-PRDM16 in the presence or absence of rosiglitazone (1uM). These samples were profiled using Affymetrix mouse 430A_2 arrays, representing 2 biological replicates for each samples (8 samples in total).

2012-03-06 | E-GEOD-35011 | biostudies-arrayexpress

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