FOXO1-KLF10 reinforcing loop promotes adipose lipolysis to facilitate exercise-induced anti-obesity effect in male mice
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ABSTRACT:
PROVIDER: PRJNA1119976 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29275354_1.fastq.gz | Fastqsanger.gz | |||
| SRR29275354_2.fastq.gz | Fastqsanger.gz | |||
| SRR29275355_1.fastq.gz | Fastqsanger.gz | |||
| SRR29275355_2.fastq.gz | Fastqsanger.gz | |||
| SRR29275356_1.fastq.gz | Fastqsanger.gz |
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Project description:Exercise is recognized to be an effective way in the combat against obesity and related metabolic disorders, but the underlying mechanism is incompletely understood. Krüppel-like factor 10 (KLF10) is a transcription factor participating in diverse biological processes. KLF10 expression is abundant in adipose tissue, but its role in obesity is not well defined. Here, we show that exercise could facilitate adipocyte-derived KLF10 expression via the SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 (KLF10AKO) blunts exercise-promoted white adipose browning, energy expenditure, fat loss, and glucose tolerance in diet-induced obese (DIO) mice. On the contrary, adipocyte-specific transgenic expression of KLF10 in mice (KLF10ATG) enhanced the abovementioned metabolic benefits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of the Pnpla2 and Lipe genes to promote the expression of these key lipolytic genes, therefore facilitating lipolysis to defend against DIO in mice. As a newfound downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity
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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:Transcriptional profiling of mouse pancreatic cancer cells comparing Pdx-1Cre LSL-KrasG12D P53L/L cells with Pdx-1Cre LSL-KrasG12D KLF10L/L P53L/L cells, and to determine the effects of KLF10 deficiency on murine PDAC gene expression.
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Project description:KrÜppel-like factor 10 (KLF10), deficient in two thirds of 105 resected pancreatic adenocarcinoma (PDAC) patients, was associated with rapid loco-regional recurrence and large tumor size. Additional KLF10 depletion in KC (LSL: KrasG12D; Pdx1-CRE) mice accelerated progression from pancreatic intraepithelial neoplasia to PDAC. In Panc-1 cells with KLF10 deficiency (Panc-1-pLKO-shKLF10), increased sphere formation, stem cell markers expression, and tumor growth were noted compared with those of control. Over-expressing KLF10 genetically or pharmacologically using metformin, reversed the stem cell phenotypes induced by KLF10 depletion. Ingenuity pathway analysis and gene set enrichment analysis showed Notch signal molecules including Notch receptors 3 and 4 were over-expressed in Panc-1-pLKO-shKLF10. KLF10 transcriptionally suppressed Notch 3 and 4 receptors by competing with ELF3, a positive regulator, for promoter binding. Downregulating Notch signal genetically or pharmacologically ameliorated stem cell phenotypes of Panc-1-pLKO-shKLF10. Elevating KLF10 expression by metformin with concomitant evodiamine, a non-toxic Notch 3 methylation stimulator, delayed murine tumor growth of PDAC with KLF10 deficiency without prominent toxicity. These results demonstrated a novel signal pathway of KLF10 in modulating stem cell phenotypes of PDAC via transcriptional regulating Notch signal pathway. Elevating KLF10 and suppressing Notch signal may cooperatively reduce PDAC tumorigenesis and malignant progression.
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Project description:Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and liver injury, has become a leading cause of end-stage liver diseases and liver transplantation. Krüppel-like factors 10 (KLF10) is a Cys2/His2 zinc finger transcription factor that regulates cell growth, apoptosis, and differentiation. However, whether it plays a role in the development and progression of chronic liver diseases like NASH remains poorly understood. In the present study, we found that KLF10 expression was selectively upregulated in the mouse models and human patients with NASH, compared with simple steatosis (NAFL). Gain- and loss-of function studies demonstrated that hepatocyte-specific overexpression of KLF10 aggravated, whereas its depletion alleviated diet-induced NASH pathogenesis in mice. Mechanistically, transcriptomic analysis and subsequent functional experiments showed that KLF10 promotes hepatic lipid accumulation and inflammation through the palmitoylation and plasma membrane localization of fatty acid translocase CD36 via transcriptionally activation of zDHHC7. Indeed, both expression of zDHHC7 and palmitoylation of CD36 are required for the pathogenic roles of KLF10 in NASH progression. Thus, our results identify an important role for KLF10 in NAFL-to-NASH development through zDHHC7-mediated CD36 palmitoylation.
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Project description:Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and liver injury, has become a leading cause of end-stage liver diseases and liver transplantation. Krüppel-like factors 10 (KLF10) is a Cys2/His2 zinc finger transcription factor that regulates cell growth, apoptosis, and differentiation. However, whether it plays a role in the development and progression of chronic liver diseases like NASH remains poorly understood. In the present study, we found that KLF10 expression was selectively upregulated in the mouse models and human patients with NASH, compared with simple steatosis (NAFL). Gain- and loss-of function studies demonstrated that hepatocyte-specific overexpression of KLF10 aggravated, whereas its depletion alleviated diet-induced NASH pathogenesis in mice. Mechanistically, transcriptomic analysis and subsequent functional experiments showed that KLF10 promotes hepatic lipid accumulation and inflammation through the palmitoylation and plasma membrane localization of fatty acid translocase CD36 via transcriptionally activation of zDHHC7. Indeed, both expression of zDHHC7 and palmitoylation of CD36 are required for the pathogenic roles of KLF10 in NASH progression. Thus, our results identify an important role for KLF10 in NAFL-to-NASH development through zDHHC7-mediated CD36 palmitoylation.
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Project description:Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important in innate immunity. Here, we show that T cell death-associated gene 51 (TDAG51/PHLDA1) is a novel coactivator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3 to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a coactivator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
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Project description:Diabetic nephropathy is the leading cause of end-stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up-regulation of its downstream target KLF10. Overexpression of KLF10 in podocytes not only represses multiple podocyte-specific markers including nephrin, but also conversely increases KDM6A expression. We further show that KLF10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM6A or KLF10 in mice significantly suppresses diabetes-induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM6A and KLF10 proteins or mRNAs are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM6A-KLF10 feedback loop may be beneficial to attenuate diabetes-induced kidney injury.
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