Enhanced glucose uptake in adipocytes despite deteriorating insulin signaling and increased autophagic flux with high fat feeding in mice
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ABSTRACT:
PROVIDER: PRJNA415808 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6217980_1.fastq.gz | Fastqsanger.gz | |||
| SRR6217980_2.fastq.gz | Fastqsanger.gz | |||
| SRR6217990_1.fastq.gz | Fastqsanger.gz | |||
| SRR6217990_2.fastq.gz | Fastqsanger.gz | |||
| SRR6217981_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Systemic glucose homeostasis is affected by adipose cell function. Still, the cellular events preceding the onset of insulin resistance in adipocytes are not yet resolved. To capture the immediate cellular changes during diet-induced expansion of cell volume and number, we characterized the initial changes in mature adipocytes during a short high fat diet (HFD) intervention. Methods: C57BL6/J male mice were fed chow diet, and switched to HFD for 2, 4, 6 or 14 days. Systemic glucose clearance was assessed by glucose tolerance test. Adipose tissue was dissected for RNA seq analysis and cell size distribution analyzed using coulter counter technique. Insulin response in isolated adipocytes was measured by glucose uptake and Western blotting of insulin signaling intermediates. Confocal microscopy was used to assess autophagic flux in cells pre-incubated with rapamycin and chloroquine. Results: Switching to HFD was accompanied by an immediate adipose cell size expansion followed by recruitment of new adipocytes. Despite an increase in both basal and insulin-stimulated glucose uptake in adipocytes, we observed a progressive decrease in insulin-stimulated activation of Protein Kinase B (PKB) Ser473, PKB Thr308 and Akt substrate of 160 (AS160) Tyr642, and onset of systemic insulin-resistance already after two days. Moreover, RNA-seq analysis of adipose tissue revealed marked changes in gene expression at day four, of which the most significant included genes directly involved in autophagy (Trp53Inp2 and Beclin1). Enhanced autophagy was observed in isolated adipocytes from HFD-fed mice, detected as an increased density of LC3-positive puncta by confocal microscopy, and increase of LC3II. Conclusions: HFD rapidly caused impaired insulin signal transduction in adipocytes, while both basal and insulin-stimulated glucose uptake increased, which support the concept of spare signaling. Interestingly, our data suggests autophagy as one of the early cellular events that could contribute to insulin resistance.
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Project description:Doxorubicin (DOX) cardiotoxicity is an important factor of heart failure. The only clinically approved drug is dexrazoxane, while its side effect of secondary malignancies severely limited its application. It is urgent to find other alternative efficacious molecular for these chemotherapy patients. Colchicine is a safe and well tolerated anti-inflammation drug which also functions in attenuating the reactive oxygen species (ROS) generation. High dose of colchicine was reported block the autophagosome-lysosome fusion in cancer cells due to its destabilization effect to the microtubule system, while how colchicine affects the autophagic flux in cardiomyocytes is largely unknown. Recent years low dose of colchicine administration was reported helpful to the patients with pericarditis, postprocedural atrial fibrillation and coronary artery disease, most of the research attributed it to its anti-inflammation effect. Whether the autophagic flux regulated by colchicine also benefits to DOX induced heart failure remains unclear. Doxorubicin (DOX) administration was used to establish heart failure models in vivo and in vitro. Results showed that DOX blocked the autophagic vacuoles degradation, leading to damaged mitochondria and ROS accumulation. Heart failure characteristics were obviously improved after low dose of colchicine administration. Mechanistically, low dose of colchicine promoted the autolysosome degradation, cleared the damaged mitochondria, and ROS accumulation induced by the DOX and as a result attenuated DOX cardiotoxicity.
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Project description:Lipid dyshomeostasis and tau pathology are found in frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). However, the relationship between lipid dyshomeostasis and tau pathology and molecular mechanisms underlying this relationship remain unclear. Using single-cell RNA-sequencing, we report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased in excitatory neurons of human neural organoids from patient-derived induced pluripotent stem cells with the MAPT R406W mutation compared to isogenic controls. Mutant neural organoids also exhibit altered lipid species, increased phosphorylated tau, and decreased neuronal activity. Increased GRAMD1B is also found in human FTLD and AD cases and PS19 tau mice. Phosphorylated tau, free cholesterol, and lipid droplets are also increased in human FTLD and AD cases. Furthermore, GRAMD1B overexpression increases pathological tau and lipid dyshomeostasis, which may be due to blocking of autophagic flux. Our findings suggest GRAMD1B may be a new player in the regulation of autophagic flux, cholesterol transport, and tau pathology in FTLD and AD.
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Project description:Miz1 is a zinc finger protein that regulates expression of cell cycle inhibitors as part of a complex with Myc. Cell cycle-independent functions of Miz1 are poorly understood. Here, we use a Nestin-Cre transgene to delete an essential domain of Miz1 in the central nervous system (Miz1ΔPOZNes). Miz1ΔPOZNes mice display cerebellar neurodegeneration characterized by the progressive loss of Purkinje cells. Chromatin immunoprecipitation sequencing and biochemical analyses show that Miz1 activates transcription upon binding to a non-palindromic sequence present in core promoters. Target genes of Miz1 encode regulators of autophagy and proteins involved in vesicular transport that are required for autophagy. Miz1ΔPOZ neuronal progenitors and fibroblasts show reduced autophagic flux. Consistently, polyubiquitinated proteins and p62/Sqtm1 accumulate in the cerebella of Miz1ΔPOZNes mice, characteristic features of defective autophagy. Our data suggest that Miz1 may link cell growth and ribosome biogenesis to the transcriptional regulation of vesicular transport and autophagy.
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