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Project description:Purpose: To study the role of PPAR nuclear receptors in brown fat. Methods: mRNA-sequencing was performed on brown adipose tissue from mice on diets with or without added rosiglitazone or fenofibrate. Sequence reads that passed quality filters were analyzed at the transcript isoform level with RNA-Seq Unified Mapper. Results: We identified genes that were induced or repressed by either PPAR agonist, and approximately three-fold more genes were significantly regulated by rosiglitazone (rosi, a PPARg agonist) than by fenofibrate (feno, a PPARa agonist). Those genes induced by either drug were enriched for expected lipid metabolic pathways, while down-regulated genes fell in pathways of uncertain relevance. Most genes were selectively regulated by one of the two PPAR agonists, with few regulated by both. Only 34 genes were induced by both PPAR agonists (~10% of rosi-induced genes and ~25% of feno-induced genes), and these were enriched for mitochondrial functionrelated pathways, including fatty acid β-oxidation. Conclusions: These data suggest that PPARγ agonists have stronger effects on BAT than PPARα agonists, yet those genes activated by both PPAR agonists may be particularly relevant to BAT function.
2020-01-30 | GSE144490 | GEO
Project description:We report the application of sequencing technology for high-throughput profiling of PPARα/γ in mammalian cells. By obtaining over 3 billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse brown adipose tissue. We find that PPARα binds to a subset of PPARγ sites, suggesting a potential redundancy in which PPARα function may not be necessary in brown adipose tissue.While PPARα may not itself be necessary for BAT function, shared targets regulation by PPARα and PPARγ may nonetheless reveal relevant biology in this tissue.This study provides a framework for the application of comprehensive chromatin profiling towards characterization of PPARα/γ regulation in mouse brown adipose tissue.
2020-01-30 | GSE144488 | GEO
Project description:Shared PPARα/γ target genes regulate brown adipocyte thermogenic function
| PRJNA603779 | ENA
Project description:Shared PPARα/γ target genes regulate brown adipocyte thermogenic function (RNA-Seq)
| PRJNA603781 | ENA
Project description:The shared PPARα/γ target genes regulate brown adipocyte thermogenic function (ChIP-Seq)
| PRJNA603784 | ENA
Project description:Brown adipocytes provide a metabolic defense against environmental cold but become dormant as mammals habituate to warm environments. Although dormancy is a regulated response in brown adipocytes to environmental warmth, its transcriptional mechanisms and functional importance are unknown. Here, we identify B cell leukemia/lymphoma 6 (BCL6) as a critical regulator of dormancy in brown adipocytes but not for their commitment, differentiation, or cold-induced activation. In a temperature-dependent manner, BCL6 suppresses apoptosis, fatty acid storage, and coupled respiration to maintain thermogenic fitness during dormancy. Mechanistically, BCL6 remodels the epigenome of brown adipocytes to enforce brown and oppose white adipocyte cellular identity. Thus, unlike other thermogenic regulators, BCL6 is specifically required for maintaining thermogenic fitness when mammals acclimate to environmental warmth.
| S-EPMC6708354 | biostudies-literature
Project description:Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high-fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes.
| S-EPMC6934193 | biostudies-literature
Project description:Brown adipose tissue contributes importantly to homeothermy and energy balance in rodents due its ability under demand to produce heat through a process denominated nonshivering thermogenesis. Such thermogenic ability of brown adipocytes relies on the activity of mitochondrial uncoupling protein 1 that, when properly activated, dissipates energy from oxidative metabolism as heat. Brown adipose tissue sympathetic innervation through norepinephrine release not only induces brown adipocyte lipolysis and thermogenesis, but also acts as the major determinant of tissue mass, cellularity and mitochondrial content. Several pieces of evidence gathered over the years indicate that, in addition to tissue sympathetic innervation, the nuclear receptor peroxisome proliferator-activated receptor γ plays an important role in regulating the development, metabolism and thermogenic function of brown adipose tissue. Herein we review the main evidence supporting such key role of peroxisome proliferator-activated receptor γ to brown fat biology and discuss the future directions of this important area of research.
| S-EPMC4843924 | biostudies-other
Project description:Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin-resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific Mfn2 knockout (Mfn2-adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2-adKO mice were protected from high-fat diet-induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole-body energy homeostasis.
| S-EPMC5452040 | biostudies-literature
Project description:Previous studies reported that Stat5 promotes adipogenesis and white adipocyte differentiation. However, the role of Stat5 in brown adipocyte development is poorly understood. We found Stat5a was higher expressed in brown adipocytes than in white adipocytes, and its level was increased during the process of brown adipocyte differentiation. In addition, Stat5a expression was affected by cold stress and high-fat diet-feeding, suggesting a potential role in thermogenesis. Knockdown of Stat5a induced downregulation of brown fat specific genes (UCP1, PGC-1α, Acox-1 and Cidea), while overexpression of Stat5a did the opposite effect. What is more, bioinformatics analysis, ChIP assay and Luciferase activity assay all verified that Stat5a directly bind and transactivate Kdm6a promoter (Lysine-specific demethylase 6A). Further, we found that Stat5a overexpression promoted the expression of Kdm6a and inhibited the trimethylation of H3K27. While inhibiting of Kdm6a reversed the promoting effect of Stat5a overexpression on the expression of brown fat specific genes. Therefore, we conclude that Stat5a participated in brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter.Abbreviations: Stat5: Signal transducers and activators of transcription 5; BAT: brown adipose tissue; WAT; white adipose tissue; eWAT: epididymal white adipose tissue; sWAT: subcutaneous white adipose tissue; SVFs: stromal vascular fractions; UCP1: Uncoupling protein 1; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Acox-1: Peroxisomal acyl-coenzyme A oxidase 1; Cidea: Cell death activator CIDE-A; ChIP: Chromatin Immunoprecipitation; HFD: High fat diet; FBS: Fetal bovine serum; siStat5a: Stat5a siRNA; siKdm6: Kdm6a siRNA; pcDNA-Stat5a: over expression of Stat5a pcDNA3.1 vector; IgG: mouse immunoglobulin G; Kdm6a: Lysine-specific demethylase 6A; H3K27me3: trimethylated H3K27.
| S-EPMC7217358 | biostudies-literature