GDF15 links beta-adrenergic induced lipolysis with anxiety
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1110190 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28992000_1.fastq.gz | Fastqsanger.gz | |||
| SRR28992000_2.fastq.gz | Fastqsanger.gz | |||
| SRR28992001_1.fastq.gz | Fastqsanger.gz | |||
| SRR28992001_2.fastq.gz | Fastqsanger.gz | |||
| SRR28991990_1.fastq.gz | Fastqsanger.gz |
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Project description:Psychological stress activates the autonomic nervous system to protect organisms through an integrated response involving changes to both behavior and metabolism. Epinephrine is an important driver of this response, activating adipose tissue lipolysis3and inducing anxiety-like behavior. Interestingly, anxiety correlates with circulating free fatty acid levels and can be alleviated by a b-blocker that does not cross the blood brain barrier suggesting a peripheral signal linking metabolism with behavior, however, to date this has not been defined. Herein, we identify that the most upregulated secreted gene product induced by epinephrine within white adipose tissue of mice is growth differentiating factor 15 (GDF15). This increase in GDF15 occurs within one hour and is not observed in liver, brown adipose, kidney, or skeletal muscle, and is also observed with the more specific b2/3-agonist, CL316,243. Genetic inhibition of adipose triglyceride lipase (ATGL), the rate limiting enzyme for the release of free fatty acids in white adipose tissue, or genetic deletion of b-adrenergic receptors, blocks b-adrenergic induced increases in GDF15. Increases in circulating GDF15 are not derived from adipocytes but instead require free fatty acid-induced stimulation of macrophages within white adipose tissue. Remarkably, anxiety-like behavior elicited by epinephrine or restraint stress are eliminated in mice lacking the GDF15 receptor, GFRAL. Importantly in patients with severe burns, increases in catecholamines are associated with GDF15 and this relationship is eliminated with the b-blocker propranolol. These data provide important insight into the mechanisms linking metabolism and behavior and suggest that inhibition of GDF15-GFRAL signaling may be important for reducing acute anxiety.
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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.
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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: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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Project description:Adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation
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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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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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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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