Biology subjects

Bennett, B. J.

Publications and source records attributed to Bennett, B. J..

4 recordsLinked to original sources

bioRxiv2026

Metabolomics highlights cardiovascular risk factor links to sphingolipid and one-carbon metabolism in asymptomatic adults

Background: Metabolic perturbations associated with cardiovascular disease (CVD) risk factors prior to clinical disease manifestation may inform novel preventative measures. Here we characterize metabolome-wide associations with various cardiometabolic risk factors in an asymptomatic population to develop a mechanistic metabolic framework of preemergent metabolic shifts. Methods: Plasma was collected from a clinically healthy cross-sectional cohort (n = 361; Clinical Trials.gov ID: NCT02367287). Cohort mass spectrometry-based metabolomics (biocrates MxP(R) Quant 500 kits) were complemented with expanded lipidomic coverage for a sex/age-matched subset with LDLc difference > 60 mg/dL (n = 38). LDLc-focused partial least square regressions and discriminate analyses were performed, after false discovery rate corrections. Results: As LDLc levels increased, plasma sphingolipids and cholesteryl esters, and transulfuration products were higher, while ether-linked phosphatidylcholines serine, glycine, alanine, methionine were lower. The subset analysis further highlighted elevations in triglycerides and deoxyceramides with elevated LDLc. When adjusted for alanine concentrations, deoxyceramide concentrations increased as serine declined (p = 0.0012), and the deoxyceramide:ceramide ratios were higher in the high LDLc group (p = 0.039). Lower serine levels were also accompanied by parallel changes in glycine (p= 0.0004), and anti-parallel changes in transsulfuration pathway metabolites particularly when adjusted for ceramide levels. Notably, the alanine:serine ratio was more strongly associated with fasting triglycerides (r = 0.38; p <0.0001) than LDLc. Conclusions: Serine depletion by increased demands of sphingolipid, and possibly transsulfuration pathway, metabolism is associated with elevations in cytotoxic deoxyceramides and reductions in glycine and methionine availability for one-carbon metabolism. These changes were strongly associated with fasting triglycerides and insulin resistance, a key marker of residual CVD risk.

biochemistry↗

bioRxiv2026

Primary-Level Meta-Analysis of Diversity Outbred Mice Identifies a Fasting Plasma Trimethylamine N-Oxide (TMAO) Locus Modified by Sex and Diet

Trimethylamine n-oxide (TMAO) is a plasma metabolite linked to adverse cardiometabolic health with complex regulation involving diet, sex, and host genetics. We explored the role of these factors in the genetic regulation of TMAO by performing a primary-level meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five distinct studies conducted in various regions of the United States. We identified a quantitative trait locus (QTL) associated with TMAO concentration at [~]86 megabase pairs on mouse chromosome 12 with a highly significant LOD score of 67.67. Alleles at the chromosome 12 QTL inherited from the Cast/EiJ (CAST) and PWK/PhJ (PWK) mouse strains primarily drove the association with reduced TMAO concentrations. The chromosome 12 QTL remained significant in sex-stratified analyses and the mode of inheritance appeared additive; furthermore, the QTL was regulated by sex-by-genotype and sex-by-diet interactions. Using a CAST/EiJ X C57BL/6J F2 cross, positional candidates were prioritized by eQTL analysis. Further analysis in a study utilizing the eight DO founding strains identified that Acyp1 was differentially expressed in hepatic tissue from CAST mice, prompting investigation into its genetic regulation. Acyp1 demonstrated relevant cis- and trans-regulation and was significantly correlated with TMAO and hepatic Fmo3. However, no significant relationships between Acyp1 and TMAO were identified in mice inactivated for Acyp1 or with AAV overexpression of Acyp1 in the liver. Genes within the chromosome 12 QTL have synteny with humans and may translate to the genetic regulation of human plasma TMAO concentrations and atherosclerosis. Author SummaryWe explored the roles of diet, sex, and genetics on the regulation of fasting plasma trimethylamine n-oxide (TMAO) concentration by performing a meta-analysis in 1,482 female and male Diversity Outbred (DO) mice from five unique studies. We identified a QTL associated with TMAO concentration on chromosome 12 at [~]86 mega base pair (Mb) with a highly significant LOD score of 67.67. The locus is modified by both sex and diet.

genetics↗

bioRxiv2025

Urinary Signatures Predict Calorie Restriction-Mediated Weight Loss in Obese Diversity Outbred Mice

Predictive analytics encompassing metabolomic profiles are increasingly being used to forecast responders to dietary interventions. Advances using this approach are particularly needed to personalize and enhance the effectiveness of dietary weight loss interventions. Using obese Diversity Outbred (DO) mice that model genetic and phenotypic heterogeneity of human populations, we aimed to identify urinary metabolite signatures predictive of responsiveness to calorie restriction (CR)-mediated weight loss. DO mice (150 males, 150 females) were fed a high-fat diet for 12 weeks to induce obesity, then urine was collected and an 8-week CR regimen (30% decrease in energy intake) initiated. At study completion, mice were rank-ordered according to their percent body weight change, with mice in the extreme quartiles deemed CR responders (n=67) versus nonresponders (n=67). Targeted semi-quantitative metabolomics identified elevated glutamic acid and hydroxyproline as key urinary metabolites that distinguish CR responders from CR nonresponders, independent of sex. Three urinary metabolites (glutamic acid, hydroxyproline, and putrescine) distinguished male CR responders from nonresponders. Six metabolites (glutamic acid, hydroxyproline, dopamine, histamine, lysine, and spermine) distinguished female CR responders from nonresponders. Multivariate receiver operating characteristic analyses integrated the common metabolites and sex-specific metabolites to reveal moderate (males) to robust (females, males plus females) prediction models of CR-mediated weight loss. Further, pathway analysis identified several metabolic pathways, including arginine and proline metabolism, and alanine, aspartate, and glutamate biosynthesis, that distinguished CR responders from nonresponders and could be indicative of metabolic reprogramming to enhance insulin sensitivity and energy metabolism.

physiology↗

bioRxiv2023

Precision pharmacological reversal of genotype-specific diet-induced metabolic syndrome in mice informed by transcriptional regulation

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genomic DNA methylation analyses and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis, as well as increased inflammatory-related gene expression changes in NOD. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.

genetics↗