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Transcriptome analysis in adipose tissues of BAF60a knockout mice

ABSTRACT: Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. BAF60a serves an indispensable role in cold-induced thermogenesis in brown fat. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced browning of inguinal white adipose tissue. These results suggest a dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs. To elucidate the mechanism, we performed microarray annalysis in inguinal white adipose tissues from mice after chronic cold exposure.

ORGANISM(S): Mus musculus

PROVIDER: GSE145498 | GEO | 2020/02/19

REPOSITORIES: GEO

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BAF60a deficiency uncouples chromatin accessibility and cold sensitivity from white fat browning

Project description:Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we found that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensible role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility for key thermogenic genes in close proximity to PPARg and EBF2 binding sites. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.

2020-02-20 | GSE128747 | GEO

Mouse Vascularized Adipose Spheroids: An Organotypic Model for Thermogenic Adipocytes

Project description:Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues’ thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by factors like cold exposure, share mechanisms that drive non-shivering thermogenesis. Understanding their behavior requires sophisticated, yet universal in vitro models that replicate the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue. We show that scaffold embedding improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to 2D cultures, which was further enhanced by β-adrenergic receptor stimulation via isoproterenol correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, our vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.

2024-05-02 | GSE261267 | GEO

A non-cell autonomous mechanism of beige adipocyte renaissance in subcutaneous adipose tissue

Project description:Two types of UCP1 positive cells-brown and beige adipocytes exist in mammals. Beige adipocytes are very plastic, and can be dynamically regulated by environment.Beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue (iWAT) lost thermogenic gene expression and multilocular morphology at adult stage, but cold could restore their “beigeing” characteristics, a phenomenon termed as beige adipocyte renaissance. Our results showed that beige cell maintenance and renaissance in adult mice were regulated by cAMP and HDAC4 signaling in white adipocytes non-cell autonomously. Genetic modulations of various components of this cAMP-HDAC4 cascade (e.g. LKB1) led to persistent browning and reduced adiposity independent of thermogenesis. To further study the mechanisms of beige adipocytes maintenance, we performed RNA-seq with samples from inguinal white adipose tissues of WT, AdipoqCre LKB1 F/F, and AdipoqCre LKB1 F/F; HDAC4 F/F mice.Our studies will move the beige adipocyte field forward and attract clinical applications to target beige adipocyte renaissance.

2018-02-14 | GSE85335 | GEO

Bulk RNA sequencing of acetylcholine-synthesizing macrophages from subcutaneous adipose tissue

Project description:We aimed to study the transcriptomic profile of acetylcholine-synthesizing adipose macrophages. Using a ChAT-eGFP reporter mouse (ChAT, or choline acetyltransferase, is the main enzyme for acetylcholine biosynthesis) acutely exposed to cold temperature, we used FACS to isolate ChAT-eGFP+ and ChAT-eGFP- macrophages from inguinal subcutaneous white adipose tissue (IWAT). We subjected these cells to bulk RNA-seq to better understand the transcriptomic landscape of cholinergic macrophages under cold stress and their role in beige fat thermogenesis.

2021-07-29 | GSE174345 | GEO

Lrpprc deficiency in brown adipocytes diminishes cold-induced thermogenesis but improves systemic metabolism

Project description:Insufficient mitochondrial quantity in brown adipose tissue (BAT) causes defective thermogenesis and positive energy balance, which is coupled with the development of obesity. Whether disturbance of mitochondrial quality affects BAT function remains unknown. Here, we describe that the brown adipocyte-specific Leucine-rich PPR motif-containing protein knockout mice (LrpprcBKO) exhibited mitochondrial electron transport chain (ETC) proteome imbalance and a complete loss of the -adrenergic-stimulated thermogenesis at room temperature (RT), due to specific reduction of mtDNA-encoded genes. However, the LrpprcBKO mice were lean at normal chow and were protected against high-fat-diet-induced metabolic abnormalities, such as obesity, insulin resistance, adipose inflammation, hepatic steatosis, and hypertriglyceridemia. The beige adipocytes in inguinal white adipose tissue were expanded in LrpprcBKO mice at RT, but not at thermoneutrality. However, BAT thermogenic defects and metabolic benefits were present in LrpprcBKO mice regardless of ambient temperatures. Collectively, our results reveal that a thermogenesis-incapable BAT with mitochondrial ETC proteome imbalance can improve systemic metabolism, suggesting BAT’s contributions to thermoregulation and systemic metabolism can be uncoupled.

2021-10-07 | PXD008798 | Pride

Next-generation sequencing facilitates quantitative analysis of T1-T4 sympathetic ganglia transcriptomes from TRKC+/-, AdNTF3-Tg and their respective wild type control mice after 1 day cold exposure at 5℃

Project description:Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.

2021-07-15 | GSE173503 | GEO

Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.

2018-07-19 | GSE110297 | GEO

A novel GPR120-dependent pathway of control brown fat activation mediated by FGF21

Project description:Brown adipose tissue (BAT) thermogenesis and the browning of white adipose tissue are important components of energy expenditure. An RNAseq-based analysis of the mouse BAT transcriptome led us to identify GPR120 as a gene induced by thermogenic activation. GPR120, a G protein-coupled receptor binding unsaturated long-chain fatty acids, is known to mediate some beneficial metabolic actions of polyunsaturated fatty acids. We show that pharmacological activation of GPR120 induces BAT activity and promotes the browning of white fat in mice, whereas GRP120-null mice show impaired browning in response to cold. n-3 polyunsaturated fatty acids induce brown and beige adipocyte differentiation and thermogenic activation, and these effects require GPR120. GPR120 activation induces the release of fibroblast growth factor-21 (FGF-21) by brown and beige adipocytes and increases blood FGF21 levels. The effects of GPR120 activation are impaired in FGF21-null mice and cells. Thus, the lipid sensor GPR120 constitutes a novel pathway of brown fat activation and involves FGF21.

2016-12-12 | GSE77534 | GEO

Neuregulin 4 mediates the metabolic benefits of mild cold exposure by promoting beige fat thermogenesis

Project description:Interorgan crosstalk via secreted hormones and metabolites is a fundamental aspect of mammalian metabolic physiology. Beyond the highly specialized endocrine cells, peripheral tissues are emerging as an important source of metabolic hormones that influence energy and nutrient metabolism and contribute to disease pathogenesis. Neuregulin 4 (Nrg4) is a fat-derived hormone that protects mice from nonalcoholic steatohepatitis (NASH) and NASH-associated liver cancer by shaping hepatic lipid metabolism and the liver immune microenvironment. Despite its enriched expression in brown fat, whether NRG4 plays a role in thermogenic response and mediates the metabolic benefits of cold exposure remain unexplored. Here we show that Nrg4 expression in inguinal white adipose tissue (iWAT) is highly responsive to chronic cold exposure. Nrg4 deficiency impairs beige fat induction and renders mice more susceptible to diet-induced metabolic disorders under mild cold conditions. Using mice with adipocyte and hepatocyte-specific Nrg4 deletion, we reveal that adipose tissue-derived NRG4, but not hepatic NRG4, is essential for beige fat induction following cold acclimation. Furthermore, treatment with recombinant NRG4-Fc fusion protein promotes beige fat induction in iWAT and improves metabolic health in diet-induced obese mice. These findings highlight a critical role of NRG4 in mediating beige fat induction and preserving metabolic health under mild cold conditions.

2024-01-01 | GSE246993 | GEO

Post-natal development of brown adipocytes in white fat: Phases independent and dependent of the ambient temperature

Project description:Decreased ambient temperature, from birth to weaning, significantly reduced fat mass (FM) and adiposity in developing mice. Changes in FM content in 10 day-old mice raised at 17°C were not accompanied by precocious induction of brown adipocytes in inguinal white adipose tissue (WAT). Brown phenotype was induced in 21 day-old mice independently of ambient temperature (17°C or 29°C) however the expression of Ucp1 and other brown fat biomarker genes was greater in animals raised at 17°C suggesting increased adaptive thermogenesis. Accordingly, we predict that the induction of brown adipocytes in WAT follows a strict developmental program and the number of potential brown adipocytes in WAT is determined genetically. Microarray analysis of gene expression was performed on inguinal white adipose tissue dissected from 10 and 21 day-old mice kept at different temperature conditions, that is, in mice maintained at 17°C or 29oC during early post-natal development.

2015-05-03 | E-GEOD-62350 | biostudies-arrayexpress

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