Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how ...HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.
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•Unbiased global analysis of T cell surface proteome remodeling during HIV infection•>100 proteins downregulated, including Nef targets SERINC3/5 and Vpu target SNAT1•β-TrCP-dependent SNAT1 downregulation acquired by pandemic SIVcpz/HIV-1 viruses•Uptake of exogenous alanine by SNAT1 critical for primary CD4+ T cell mitogenesis
Viruses manipulate host factors to enhance their replication. Matheson et al. use functional proteomics to analyze plasma membrane proteins downregulated during HIV-1 infection. Serine carriers SERINC3/5 and alanine transporter SNAT1 were identified as Nef and Vpu targets, respectively. Antagonism of SNAT1-mediated alanine transport enables viral interference with T cell immunometabolism
Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat ...obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.
Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we ...performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.
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•Risk of diabetes and obesity in mice is associated with differences in gut bacteria•Effects of diet, host genetics, and the microbiome are reflected in the metabolome•18 plasma metabolites correlate with insulin resistance across strains and diets•More than 1,000 unidentified MS peaks are also regulated by diet, genes, and the gut microbiota
Fujisaka et al. show that mice with differing propensities to obesity and diabetes have differing metabolomic responses to diet and antibiotic treatment. Several serum metabolites correlate with changes in the gut microbiota or with insulin resistance across strains. Thus, diet, genetics, and the gut microbiota interact to create distinct plasma metabolomic responses.
Selenium (Se) is an essential trace element because of its presence in selenoproteins in the form of selenocysteine residue. Both Se deficiency, which compromises selenoprotein functions, and excess ...Se, which is toxic, have been associated with altered redox homeostasis and adverse health conditions. Surprisingly, we found that, although Se deficiency led to a drastic decline in selenoprotein expression, mice subjected to this dietary regimen for their entire life had normal lifespans. To understand the molecular mechanisms involved, we performed systemic analyses at the level of metabolome, transcriptome, and microRNA profiling. These analyses revealed that Se deficiency reduced amino acid levels, elevated mononucleotides, altered metabolism, and activated signaling pathways linked to longevity-related nutrient sensing. The data show that the metabolic control associated with nutrient sensing coordinately responds to suppressed selenoprotein functions, resulting in normal lifespan under Se deficiency.
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•Se deficiency reduces selenoprotein expression but does not affect lifespan of mice•Se deficiency reduces amino acid levels and elevates mononucleotides•Se deficiency activates pathways linked to nutrient sensing•Se deficiency is associated with pro-longevity mechanisms
Yim et al. report that selenium deficiency in mice is associated with pro-longevity mechanisms because of reduced amino acid levels and altered nutrient signaling.
Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We ...infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.
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•Metabolic phenotyping of tumors can identify essential metabolic pathways•Kras-driven lung tumors require pyruvate carboxylase and pyruvate dehydrogenase•Kras-driven lung tumors are less dependent on glutaminase than cultured cells•Tissue environment is an important determinant of tumor metabolic phenotypes
Davidson et al. find that lung cancer cells in culture use nutrients differently than lung tumors, especially regarding glutamine metabolism. This difference in metabolic phenotype reflects how the tumor environment determines nutrient dependency and highlights the importance of studying cancer metabolism in a physiological context.
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to ...exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
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•β-aminoisobutyric acid (BAIBA) is secreted from PGC-1α-expressing myocytes•BAIBA activates the thermogenic program in white adipocytes via PPARα•Circulating BAIBA levels in mice and humans are increased with exercise•BAIBA is inversely correlated with cardiometabolic risk factors in humans
Roberts et al. use metabolic profiling to identify β-aminoisobutyric acid (BAIBA) as a PGC-1α-responsive small molecule myokine that induces β-oxidation in hepatocytes and the browning of white adipose tissue. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors.
Uncovering the molecular context of dysregulated metabolites is crucial to understand pathogenic pathways. However, their system-level analysis has been limited owing to challenges in global ...metabolite identification. Most metabolite features detected by untargeted metabolomics carried out by liquid-chromatography-mass spectrometry cannot be uniquely identified without additional, time-consuming experiments. We report a network-based approach, prize-collecting Steiner forest algorithm for integrative analysis of untargeted metabolomics (PIUMet), that infers molecular pathways and components via integrative analysis of metabolite features, without requiring their identification. We demonstrated PIUMet by analyzing changes in metabolism of sphingolipids, fatty acids and steroids in a Huntington's disease model. Additionally, PIUMet enabled us to elucidate putative identities of altered metabolite features in diseased cells, and infer experimentally undetected, disease-associated metabolites and dysregulated proteins. Finally, we established PIUMet's ability for integrative analysis of untargeted metabolomics data with proteomics data, demonstrating that this approach elicits disease-associated metabolites and proteins that cannot be inferred by individual analysis of these data.
Recent animal and small clinical studies have suggested depression is related to altered lipid and amino acid profiles. However, this has not been examined in a population-based sample, particularly ...in women. We identified multiple metabolites associated with depression as potential candidates from prior studies. Cross-sectional data from three independent samples of postmenopausal women were analyzed, including women from the Women's Health Initiative-Observational Study (WHI-OS, n = 926), the WHI-Hormone Trials (WHI-HT; n = 1,325), and the Nurses' Health Study II Mind-Body Study (NHSII-MBS; n = 218). Positive depression status was defined as having any of the following: elevated depressive symptoms, antidepressant use, or depression history. Plasma metabolites were measured using liquid chromatography-tandem mass spectrometry (21 phosphatidylcholines (PCs), 7 lysophosphatidylethanolamines, 5 ceramides, 3 branched chain amino acids, and 9 neurotransmitters). Associations between depression status and metabolites were evaluated using multivariable linear regression; results were pooled by random-effects meta-analysis with multiple testing adjustment using the false discovery rate (FDR). Prevalence rates of positive depression status were 24.4% (WHI-OS), 25.7% (WHI-HT), and 44.7% (NHSII-MBS). After multivariable adjustment, positive depression status was associated with higher levels of glutamate and PC 36 : 1/38 : 3, and lower levels of tryptophan and GABA-to-glutamate and GABA-to-glutamine ratio (FDR-p < 0.05). Positive associations with LPE 18 : 0/18 : 1 and inverse associations with valine and serotonin were also observed, although these associations did not survive FDR adjustment. Associations of positive depression status with several candidate metabolites including PC 36 : 1/38 : 3 and amino acids involved in neurotransmission suggest potential depression-related metabolic alterations in postmenopausal women, with possible implications for later chronic disease.
Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain ...pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD.
The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ≤7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design.
The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83,
<0.001), 1.91 (1.21-3.01,
=0.003), 1.97 (1.21-3.20,
=0.004), and 1.73 (1.09-2.74,
=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36-3.49;
<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (
=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up.
Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD.
URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response ...to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.
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