Fasting response of mouse brain
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72987 | GEO | 2015/11/14
SECONDARY ACCESSION(S): PRJNA295531
REPOSITORIES: GEO
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Project description:Endothelial cells (ECs) not only form passive blood conduits. They actively contribute to nutrient transport and establish an instructive vascular niche to maintain and restore organ homeostasis. The role of the endothelium in the maintenance of muscle glucose homeostasis is however poorly understood. Here we show that, in skeletal muscle, the endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake not via affecting transendothelial glucose transport, but via vascular niche control of muscle resident macrophages. Lowering endothelial glut1 via genetic depletion (glut1EC) or upon short-term high-fat diet increased angiocrine osteopontin (OPN/SPP1) secretion, promoting resident muscle macrophage activation and proliferation which impairs muscle insulin sensitivity. Consequently, co-deleting Spp1 from the endothelium prevented macrophage accumulation, reduced muscle OPN levels, and improved insulin sensitivity in glut1EC mice. Mechanistically, glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a niche that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the development of muscle insulin resistance.
2024-07-26 | GSE263417 | GEO
Project description:Endothelial cells (ECs) not only form passive blood conduits. They actively contribute to nutrient transport and establish an instructive vascular niche to maintain and restore organ homeostasis. The role of the endothelium in the maintenance of muscle glucose homeostasis is however poorly understood. Here we show that, in skeletal muscle, the endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake not via affecting transendothelial glucose transport, but via vascular niche control of muscle resident macrophages. Lowering endothelial glut1 via genetic depletion (glut1EC) or upon short-term high-fat diet increased angiocrine osteopontin (OPN/SPP1) secretion, promoting resident muscle macrophage activation and proliferation which impairs muscle insulin sensitivity. Consequently, co-deleting Spp1 from the endothelium prevented macrophage accumulation, reduced muscle OPN levels, and improved insulin sensitivity in glut1EC mice. Mechanistically, glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a niche that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the development of muscle insulin resistance.
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Project description:Short-term fasting elicits beneficial effects in mice and humans, including protection from chemotherapy toxicity, but the involved mechanisms are not well understood. We collected blood samples from healthy human volunteers and mice before and after 36 or 24 hours of fasting, respectively, to measure fatty acid composition of erythrocyte membranes, circulating miRNAs, and RNA expression at PBMCs. In both mice and humans, fasting affected the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane. Also, fasting significantly reduced the expression at PBMCs of insulin signaling-related genes, including the SREBP lipid-metabolizing pathway, in correlation with changes in membrane fatty acids. We tested the relevance of these fatty acid homeostasis parameters using a complete platform to monitor chemotherapy toxicity in mice. When fasted for 24 hours before and 24 hours after administration of the chemotherapeutic drug oxaliplatin, mice showed a strong protection from kidney, liver, heart and bone marrow toxicity. Importantly, the newly discovered fasting parameters defined two clearly separated groups of individuals that accurately predicted a differential protection from chemotherapy toxicity. Our results reveal a novel mechanism of fasting associated with fatty acids homeostasis, and provide novel biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.
2022-06-12 | GSE173241 | GEO
Project description:The effects of fasting have been studied extensively, predominantly on isolated processes, within a specific organ. No comprehensive study of the adaptations was available for different organs, let alone interrelating them, which left the understanding of the body’s orchestration of fasting response limited. The gene expression profiles of brain, small intestine, kidney, liver and skeletal muscle were therefore studied in mice subjected to short, moderate and prolonged fasting. Functional category enrichment, network, and text-mining analyses were employed to scrutinize the overall adaptive response, aiming to identify responsive pathways, processes and networks, and their regulation. The implicated processes did not follow the accepted carbohydrate-lipid-protein succession of energy substrates expenditure. Instead, they were activated simultaneously in different organs during the whole duration of fasting. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney, which showed biochemically similar, orchestrated responses. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, tied in with increased proteolysis in the muscle. Enhanced defence against oxidative damage, obvious in all the organs, was the top reaction of the brain, otherwise shown to be extremely well protected from starvation. The major transcription regulators of fasting response in different organs were FoxO transcription factors, AP-1, p53, cMyc, Sp1, EGF and HNF4α. The revealed interorgan interactions between metabolic, inflammatory and cell turnover responses are essential when designing strategies to treat the starvation affected individuals, while stressing the significance of using complimentary bioinformatics tools in the high-throughput data analysis. 6 week-old male FVB mice were fasted for 0, 12, 24, 48 or 72 hours before sacrifice (N = 5 per group). From each mouse total RNA was isolated from five organs - liver, small intestine, kidney, brain, and calf muscle. Five microarrays per experimental condition (five tissues, five timepoints) were performed. We used a common reference design. The single common-reference sample was a pool of equal amounts of RNA from all the samples investigated, including additional samples from 5 mice that were fasted for 48 hours and supplemented with vitamin B complex after 24 and 36 hours of fasting.
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2014-06-03 | E-GEOD-52982 | biostudies-arrayexpress
Project description:Macrophages (MΦs) are heterogeneous and metabolically flexible with metabolism strongly affecting immune activation. A classic response to pro-inflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, while alternative activation is primarily oxidative which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow derived MΦs (BMDM) from Slc2a1M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and Pentose Phosphate Pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1 demonstrating an incomplete metabolic reprogramming. Slc2a1M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically-activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1M-/- BMDMs had reduced pro-inflammatory metabolites, whereas metabolites indicative of alternative activation - such as ornithine and polyamines - were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr-/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1M-/- BMDMs may have contributed to unstable atheroma formation. Together our findings suggest that while lack of GLUT1 blunted glycolysis and PPP, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated yet phagocytic defects hindered MΦ function in chronic diseases. Control mice are noted as WT or Slc2a1 fl/fl and myeloid GLUT1 deficient are KO or Slc2a1M-/- (LysMCre X Slc2a1fl/fl) for myeloid deficiency.
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Project description:This study utilized AgRP+/- and AgRP-/- mice either under fed or 30h fasted conditions, to reveal genes that are regulated by fasting and AgRP.
2022-05-10 | GSE139148 | GEO
Project description:Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing identified multiple SI stem cell populations, marked by Lgr5, Bmi1 or HopX expression, that contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy. Intestines were harvested 3 h post-etoposide injection, flushed with PBS, and then flushed with ice-cold Methacarn (60% methanol, 30% chloroform, 10% acetic acid) to fix the tissue while preserving RNA integrity. Fixed intestines were rinsed with 70% ethanol, embedded in 2% agar followed by paraffin embedding. Sections were deparrafinized and dehydrated through xylene and an increasing gradient of ethanol. Laser capture microdissection was performed using the Acturus PixCell IIe, with the following settings: spot size power 80, duration 1 ms, repeat 0.2 s, target 0.150 V, current 1.82 mA. RNA was isolated from the CapSure HS LCM Caps (Applied Biosystem) using the PicoPure RNA Isolation kit (Applied Biosystems). All RNA samples were treated with DNaseI (Qiagen). Four biological replicates were used for each of the following treatments: Fasted Etoposide, Fed Etoposide. Each group had 2 male and 2 females samples. 4-6 week old Lgr5EGFP-IRES-CreERT2/+ mice were dosed with 80mg/kg etoposide (i.v.).
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