Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver

Torre, Sara Della; Mitro, Nico; Meda, Clara; Lolli, Federica; Pedretti, Silvia; Barcella, Matteo; Ottobrini, Luisa; Metzger, Daniel; Caruso, Donatella; Maggi, Adriana

doi:10.1016/j.cmet.2018.05.021

Cited by 129 publications

(132 citation statements)

References 51 publications

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“…S5D). We find that glycolysis and gluconeogenesis are modulated by gender at a pathway level, a finding that has been observed by others [44]. These control data also revealed metabolites with different concentrations in WT animals at ZT10 vs. ZT22.…”

Section: Metabolomic Studies Support the Importance Of Cbs-cry1 Intersupporting

confidence: 88%

CRY1-CBS binding regulates circadian clock function and metabolism

Cal-Kayitmazbatir¹,

Kulkoyluoglu-Cotul

Growe

et al. 2020

Preprint

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AbstractCircadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here we report that Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein Cryptochrome1 (CRY1). In cells, CBS augments CRY1 mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic CbsZn/Zn mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1−/− mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, CbsZn/Zn, Cry1−/−, and Cry2−/− samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1 induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.

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Section: Metabolomic Studies Support the Importance Of Cbs-cry1 Intersupporting

confidence: 88%

CRY1-CBS binding regulates circadian clock function and metabolism

Cal-Kayitmazbatir¹,

Kulkoyluoglu-Cotul

Growe

et al. 2020

Preprint

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“…A sex-specific metabolic difference was reported in the liver but not in the muscle or adipose tissue of mice. Liver maintains the synthesis of lipid molecules at the expense of amino acids during short-time fasting in females 65 . In a fasting state, liver in females tends to synthesize fatty acids and triglycerides and store them as fat.…”

Section: Discussionmentioning

confidence: 99%

Postprandial Metabolism is Impaired in Overweight Normoglycemic Young Adults without Family History of Diabetes

Kumar

Satheesh

Vijayakumar

et al. 2020

Sci Rep

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Markers of inflammation and T2DM. Plasma levels of obesity/T2DM related markers [Interleukin 6 (IL-6), C-peptide, Glucagon, Insulin, Leptin, Plasminogen Activator Inhibitor-1 (PAI-1), Resistin, Visfatin, Ghrelin, Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon-like peptide-1 (GLP-1), and Adiponectin] were measured using Bio-Plex Pro Human Diabetes Assay panel, Bio-Rad, following the manufacturer's protocol 18. A detailed protocol is provided with supplementary materials. plasma sample preparation and metabolomics analysis. An Ultra-Performance Liquid Chromatography, ACQUITY UPLC System (Waters) coupled to a Quadrupole-Time of Flight (Q-TOF) mass spectrometer (SYNAPT-G2 HDMS, Waters) was used for untargeted metabolomics analysis. An analytical batch comprised of equal number of samples from all the study groups and their run order was randomized within a batch. The Quality control samples were prepared by pooling equal volume of aliquots from all the samples. QC samples were analyzed after every 5 th sample run. The features detected in <50% of the QC samples and <20% of the experimental samples were removed to exclude metabolites with poor repeatability in the metabolomics data. After normalization, features with a relative standard deviation of <30% in the QC samples were used for further statistical analysis. Detailed sample preparation, liquid chromatography, and tandem mass spectrometry protocol, data transformations, and metabolite identification are provided with the supplementary materials.

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“…Application of the bioavailable fraction equation to the whole-blood radioactivity PET image curves for modeling purposes was matched by gender instead of mouse strain which, at first-glance, denotes a major limitation. Significant gender differences have been reported in highly relevant metabolic rates and enzyme expression in the liver which is the organ primarily responsible for amino acid processing [33,34] which we considered to justify the grouping. Further, the main gender metabolism difference is visible (Suppl.…”

Section: Discussionmentioning

confidence: 99%

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

et al. 2020

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Purpose: The glutamine analogue (2S, 4R)-4-[ 18 F]fluoroglutamine ([ 18 F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice. Procedures: [ 18 F]FGln was synthesized at a high radiochemical purity as analyzed by highperformance liquid chromatography. An orthotopic model was created by injecting luciferaseexpressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1 nu mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1 nu/nu mice. Dynamic PET images were acquired after injecting 10-12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1 nu/nu and 6 C57BL/6J mice was performed after 9-14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived wholeblood radioactivity and apply the data to multiple pharmacokinetic models. Results: Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle (flank) ratio of 1.9 ± 0.7 (range 1.3-3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake. Conclusions: The results reinforce that [ 18 F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.

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Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver

Cited by 129 publications

References 51 publications

CRY1-CBS binding regulates circadian clock function and metabolism

CRY1-CBS binding regulates circadian clock function and metabolism

Postprandial Metabolism is Impaired in Overweight Normoglycemic Young Adults without Family History of Diabetes

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

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