Clary Clish

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization of the ischemic neuroretina. Here we show that metabolic shifts in the neurovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.

BackgroundLung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants.MethodsWe utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and …

BackgroundThe health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood.ObjectivesOur goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors.MethodsA total of 400 participants (200 from each study group), aged 55–75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry …

MethodsUntargeted metabolomic profiling was conducted on plasma samples from 4 timepoints during a longitudinal peanut OIT interventional trial in children ages 7-18. After OIT, participants were challenged before and after a 4-week avoidance period and categorized as either having persistent protection (sustained unresponsiveness (SU)) or loss of protection (transient desensitization (TD)). Using linear and logistic regression and time series analyses, we identified changes in metabolites and pathways associated with (1) OIT over time, and (2) differences between SU and TD participants.ResultsWe identified decreases in arachidonic acid (p= 1.3 e-23) and linoleic acid (p= 1.0 e-04) pathways during OIT. Comparing SU versus TD revealed differing concentrations of bile acid (p= 3.7 e-08), arachidonic acid (p= 3.2 e-09), and histidine pathways. Notably, the bile acid metabolite, lithocholate (3.48 [1.53, 9.24], p …

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and …

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancer types. A key — yet poorly understood — facet in the disease state is cachexia, a multi-organ pathological state characterized by physical wasting and tissue catabolism. It occurs in 80% of PDAC patients, and to date there are no preventative or early detection methods. Cachexia leads to limited tolerance to anti-cancer therapy and contributes to disease lethality. Here, we present the first-of-its-kind systemic metabolomic analysis across cachectic stages to better understand disease progression. We used the well-established mutant KRASG12D(LSL/+) mutant p53 inducible mouse model of PDAC. Model physiology faithfully recaptures human cachexia: we observe progressive overall weight loss as well as loss of skeletal muscle and adipose tissue. As with human disease, weight loss occurs prior to loss of appetite in the animals …

BackgroundDistinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis.ObjectivesWe investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates.MethodsThis study included adults with overweight or obesity (n=536) who participated in a randomized weight-loss diet intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 months after weight-loss diet interventions. The ASCVD risk estimates were calculated by the validated equations.ResultsAt baseline, higher levels of specific BA subtypes were related to higher levels of atherogenic VLDL lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in …

BackgroundMetabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion.MethodsThe study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was …

BackgroundGut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear.MethodsWe first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV+) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained …

Rationale Published studies of vitamin A and lung function in asthma have yielded conflicting findings, possibly due to competition with the vitamin D receptor, which is shared with retinol. We hypothesized that the complex relationship between vitamin A, vitamin D, and lung function in children with asthma would be under epigenetic regulation by microRNA. MethodsIn two childhood asthma cohorts, Genetics of Asthma in Costa Rica Study (GACRS, N= 1121, ages 6-14 year) and Childhood Asthma Management Program (CAMP, N= 454, ages 5-12 year), we measured plasma 9-cis retinoic acid (active vitamin A) using untargeted metabolomic profiling (Metabolon Inc.). We sequenced serum miRNA data from 1121 CRA and 491 CAMP subjects using Illumina NextSeq 500. Multivariate linear regression was employed to assess the association between plasma vitamin A levels and lung function (FEV1, FVC and …

Background: Ovarian cancer has a poor prognosis with a 5-year survival less than 50%, resulting > 14,000 deaths in the US annually and > 150,000 globally. Identifying prognostic biomarkers at time of diagnosis and elucidating the biological dysregulation among those who are more likely to progress after first-line treatment could inform personalized treatment strategies. Thus, we evaluated metabolites and metabolomic profiles in pretreatment blood associated with survival in women with high-grade serous ovarian cancer, the most common and most deadly histologic subtype. Method: We examined plasma metabolites in blood samples collected prior to ovarian cancer treatment in 80 high-grade serous ovarian cancer patients who participated in the PreOperative Pelvic Mass Study, a clinic-based study enrolling women undergoing surgery for a pelvic mass. Liquid chromatography tandem mass spectrometry …

This study introduces a multidisciplinary approach to investigate bioactive food metabolites often overlooked due to their low concentrations. We integrated an in-house food metabolite library (n = 494), a human metabolite library (n = 891) from epidemiological studies, and metabolite pharmacological databases to screen for food metabolites with potential bioactivity. We identified six potential metabolites, including meglutol (3-hydroxy-3-methylglutarate), an understudied low-density lipoprotein (LDL)-lowering compound. We further focused on meglutol as a case study to showcase the range of characterizations achievable with this approach. Green pea tempe was identified to contain the highest meglutol concentration (21.8 ± 4.6 mg/100 g). Furthermore, we identified a significant cross-sectional association between plasma meglutol and lower LDL cholesterol in two Hispanic adult cohorts (n = 1,628) (β …

Objective:The perturbation of tryptophan (TRP) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis remain unclear in the context of HIV infection.Methods:We included 361 women (241 HIV+, 120 HIV−) with carotid artery plaque assessments from the Women's Interagency HIV Study, measured 10 plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolite-related gut bacteria were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. Associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression.Results:Although plasma kynurenic acid (KYNA)[odds ratio (OR)= 1.93, 95% confidence interval (CI): 1.12–3.32 per one SD increase; P= 0.02) and KYNA/TRP [OR= 1.83 (95% CI 1.08 …

BACKGROUND High levels of lipoprotein (a)[Lp (a)] are a causal risk factor for cardiovascular disease. Lp (a) levels are primarily determined genetically, around 90%. Although Lp (a) remains a risk factor for cardiovascular disease, little is known about how individuals with genetically elevated levels of Lp (a) respond to exercise training. Purpose This research investigates whether the cardiometabolic responses to exercise differs based on LPA genotype. METHODS We measured LPA genotype (SNP rs3798220) and phenotypes in 670 Black and White participants of the HERITAGE Family Study who completed 20 weeks of exercise training. Phenotypes were measured before and after training, including body composition, cardiopulmonary exercise tests, lipid panels, inflammatory markers, and measures of glucose homeostasis. Student’s t-tests and general linear models were used to determine whether mean training-induced changes in phenotypes differed between LPA genotypes. P< 0.05 was used to determine significance. RESULTS At baseline, individuals with genetically predicted high levels of Lp (a)(rs3798220 CT genotype, n= 24) had a generally worse cardiometabolic profile (eg, higher concentration of triglycerides, apoB, and small LDL) compared to the TT genotype (n= 646). For several phenotypes both LPA genotypes experienced similar improvements in response to training, including increases in VO2max and HDL-C and decreases in submaximal exercise blood pressure (all p< 0.05 for within group changes). However, the rs3798220 CT genotype group experienced some training responses in an unexpected direction …

Rationale Chronic obstructive pulmonary disease (COPD) patients demonstrate marked heterogeneity with respect to emphysema, mortality, exacerbations, lung function decline, and other disease-related outcomes. Omic Scores (OS) estimate the cumulative contribution for omics such as the transcriptome, proteome, and metabolome to a particular trait. In this study, we aimed to assess the predictive value of OSs for COPD-related traits in both smoking-enriched and general population cohorts. Methods We included Genetic Epidemiology of COPD (COPDGene) and Multi-Ethnic Study of Atherosclerosis (MESA) participants with RNA-sequencing, proteomic, and metabolomic data. We split COPDGene into training and testing datasets (80: 20). Within the training set, we constructed OS using elastic net regression (with 10-fold cross-validation) for the following traits/outcomes measured coincident with omics …

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

A high glycemic index (HGI) diet induces hyperglycemia, a risk factor for diseases affecting multiple organ systems. Here, we evaluated tissue-specific adaptations in the liver and retina after feeding HGI diet to mice for 1 or 12 month. In the liver, genes associated with inflammation and fatty acid metabolism were altered within 1 month of HGI diet, whereas 12-month HGI diet-fed group showed dysregulated expression of cytochrome P450 genes and overexpression of lipogenic factors including Srebf1 and Elovl5. In contrast, retinal transcriptome exhibited HGI-related notable alterations in energy metabolism genes only after 12 months. Liver fatty acid profiles in HGI group revealed higher levels of monounsaturated and lower levels of saturated and polyunsaturated fatty acids. Additionally, HGI diet increased blood low-density lipoprotein, and diet-aging interactions affected expression of mitochondrial oxidative …

Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex interactions among metabolism, aging, and systems‐wide phenotypes across the lifespan. Among 2469 adults (mean age 74.7 years; 38% Black) in the Health, Aging and Body Composition study we identified metabolic cross‐sectionally correlates across 20 multi‐dimensional aging‐related phenotypes spanning seven domains. We used LASSO‐PCA and bioinformatic techniques to summarize metabolome‐phenome relationships and derive metabolic scores, which were subsequently linked to healthy aging, mortality, and incident outcomes (cardiovascular disease, disability, dementia, and cancer) over 9 years. To clarify the relationship of metabolism in early adulthood to aging, we tested association of these …

The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to …

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ~40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic …