Project description:To elucidate the sex-specific role of PGC1α in brown adipose tissue (BAT), we performed RNA-seq analysis on BAT from male and female PGC1α knockout mice. Furthermore, to investigate the effects of estrogen on BAT, we conducted RNA-seq analysis on BAT from male and female wild-type mice treated with tamoxifen.
Project description:To elucidate the sex-specific role of PGC1α in brown adipose tissue (BAT), we performed ATAC-seq analysis on BAT from male and female PGC1α knockout mice.
Project description:We reported that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, beige adipocyte differentiation and activation. Mechanistically, Naa10p acetylates the N-terminus of Pgc1α and prevents it from interacting with Ppar to activate key genes, such as Ucp1, involved in beige adipocyte function. We used microarrays to profile the gene expression changes by Naa10p KO in inguinal white adipose tissues (iWATs) derived from mice fed with high fat diet for 15 weeks.
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
Project description:Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Epigenetic regulation has emerged as a key mechanism underlying BAT development and function. To study the epigenetic regulation of BAT thermogenesis, we surveyed the expression of epigenetic enzymes that catalyze histone modifications in developmental beige adipocytes and found a unique expression pattern of suppressor of variegation 4-20 homolog 2 (Drosophila) (Suv420h2), a histone methyltransferase that preferentially catalyzes the tri-methylation at histone H4 lysine 20 (H4K20me3), a hallmark of gene silencing. Here we discovered that Suv420h2 expression parallels that of UCP1 expression in brown and beige adipocytes and that SUV420H2 knockdown significantly reduces, whereas SUV420H2 overexpression significantly increases UCP1 levels in brown adipocytes. Suv420h2 knockout (H2KO mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study showed that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) promoter, leading to down-regulated expression of 4E-BP1, a negative regulator of the translation initiation complex. This in turn up-regulates PGC1α protein levels, which is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.
Project description:Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC1α) is a coactivator of various nuclear receptors and other transcription factors that shows increased expression in skeletal muscle during exercise. In skeletal muscle, PGC1α is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Several isoforms of PGC1α mRNA have recently been identified. PGC1α-a is a full-length isoform of PGC1α that was the first to be isolated. PGC1α-b is another isoform of PGC1α, which is considered to be similar in function to PGC1α-a, differing by only 16 amino acids at the amino terminus. We have previously generated independent lines of transgenic mice that overexpress PGC1α-a or PGC1α-b in skeletal muscle. The microarray data shows that energy metabolism-related pathways such as the TCA cycle, branched-chain amino acid metabolism, purine nucleotide pathway, and malate–aspartate shuttle are activated in PGC1α transgenic mice compared with wild-type mice. For microarray analysis, RNA was isolated from the gastrocnemius skeletal muscle of wild-type control mice (12 weeks of age) as well as transgenic mice [PGC1α-a (E) (Miura et al., J. Biol. Chem. 278:31385-90, 2003), 12 weeks of age; PGC1α-b (02-1) (Miura et al., Endocrinology 149:4527-33, 2008), 14 weeks of age; and PGC1α-b (03-2) (Miura et al., Endocrinology 2008), 14 weeks of age]. Samples from wild-type and transgenic mice (N = 5 for each group) were pooled before use.
Project description:Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.