Adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA597001 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10745757.fastq.gz | Fastqsanger.gz | |||
| SRR10745758.fastq.gz | Fastqsanger.gz | |||
| SRR10745759.fastq.gz | Fastqsanger.gz | |||
| SRR10745760.fastq.gz | Fastqsanger.gz | |||
| SRR10745761.fastq.gz | Fastqsanger.gz |
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Project description:Beta-adrenergic stimulation stabilizes ERK3, resulting in the formation of a complex with MK5 and thereby driving lipolysis. A downstream target of the complex is FOXO1, which controls expression of the lipolytic enzyme ATGL. Deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation.
2021-01-01 | GSE142424 | GEO
Project description:Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.
| S-EPMC7111262 | biostudies-literature
Project description:Obesity is associated with impaired β-adrenergic receptor (Adrb1-3) signaling and lipolysis, leading to aberrant white adipose tissue (WAT) growth. WAT research has been centered on transcriptional and posttranslational regulations, but posttranscriptional regulation and mRNA modifications are poorly understood. Here, we unveil a METTL14/N6-methyladenosine (m6A) paradigm guiding β-adrenergic signaling and lipolysis. METTL14 complex installs m6A on RNA, regulating mRNA fate and translation. We found that feeding and insulin increased adipose Mettl14 and m6A levels. Adipose Mettl14 and m6A were upregulated in high fat diet (HFD)-induced obesity. Ablation of adipose Mettl14 decreased Adrb2, Adrb3, Atgl (encoding lipase), and Cig-58 (Atgl activator) transcript m6A contents while increasing their translation and protein levels, thereby enhancing adipose β-adrenergic signaling and lipolysis. Consequently, adipocyte-specific Mettl14 knockout mice were resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and NAFLD. These results unravel a METTL14/m6A-based epitranscriptomic mechanism governing β-adrenergic signaling, lipolysis, and adipose growth in health and disease.
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Project description:GDF15 links beta-adrenergic induced lipolysis with anxiety
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Project description:Establishment and maintenance of epithelial architecture are essential for embryonic development and adult physiology. Here, we show that ERK3, a poorly characterized atypical MAPK, regulates epithelial architecture in vertebrates. In Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight junction protein distribution, as well as tight junction barrier function, resulting in epidermal breakdown. Moreover, in human breast epithelial cancer cells, inhibition of ERK3 expression induces thickened epithelia with aberrant adherens and tight junctions. Microarray results suggest an involvement of TFAP2A, a transcription factor important for epithelial gene expression, in ERK3-dependent gene expression changes. TFAP2A knockdown phenocopies ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 is required for full activation of TFAP2A-dependent transcription. Our findings thus reveal that ERK3 regulates epithelial architecture, possibly in cooperation with TFAP2A. We used microarrays to study the changes in ERK3-dependent gene expression profiles during pronephros and epidermal development in Xenopus laevis embryos.
2018-06-13 | GSE110427 | GEO
Project description:Establishment and maintenance of epithelial architecture are essential for embryonic development and adult physiology. Here, we show that ERK3, a poorly characterized atypical MAPK, regulates epithelial architecture in vertebrates. In Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight junction protein distribution, as well as tight junction barrier function, resulting in epidermal breakdown. Moreover, in human breast epithelial cancer cells, inhibition of ERK3 expression induces thickened epithelia with aberrant adherens and tight junctions. Microarray results suggest an involvement of TFAP2A, a transcription factor important for epithelial gene expression, in ERK3-dependent gene expression changes. TFAP2A knockdown phenocopies ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 is required for full activation of TFAP2A-dependent transcription. Our findings thus reveal that ERK3 regulates epithelial architecture, possibly in cooperation with TFAP2A. We used microarrays to compare the changes in ERK3-dependent gene expression profiles with those in TFAP2A-dependent gene expression profiles in Xenopus laevis embryos.
2018-06-13 | GSE110428 | GEO
Project description:β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. Here we have used pharmacological inhibitors and a novel direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in brown adipocytes. We show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on brown adipocyte transcription and function.
2022-05-15 | GSE202833 | GEO
Project description:β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. Here we have used pharmacological inhibitors and a novel direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in brown adipocytes. We show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on brown adipocyte transcription and function.
2022-05-21 | GSE203247 | GEO
Project description:β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. Here we have used pharmacological inhibitors and a novel direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in brown adipocytes. We show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on brown adipocyte transcription and function.
2022-05-15 | GSE202834 | GEO
Project description:β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. Here we have used pharmacological inhibitors and a novel direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in brown adipocytes. We show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on brown adipocyte transcription and function.
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