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Diabetes Care Jun 2023To identify a postpartum lipidomic signature associated with gestational diabetes mellitus (GDM) and investigate the role of the identified lipids in the progression to...
OBJECTIVE
To identify a postpartum lipidomic signature associated with gestational diabetes mellitus (GDM) and investigate the role of the identified lipids in the progression to type 2 diabetes (T2D).
RESEARCH DESIGN AND METHODS
This prospective cohort study enrolled 1,409 women at 24-72 h after delivery of a singleton baby and followed them prospectively at the Boston Medical Center. The lipidome was profiled by liquid chromatography-tandem mass spectrometry. Diagnoses of GDM and incident T2D were extracted from medical records and verified using plasma glucose levels.
RESULTS
Mean (SD) age of study women at baseline was 28.5 (6.6) years. A total of 219 (16.4%) women developed incident diabetes over a median follow-up of 11.8 (interquartile range 8.2-14.8) years. We identified 33 postpartum lipid species associated with GDM, including 16 inverse associations (primarily cholesterol esters and phosphatidylcholine plasmalogens), and 17 positive associations (primarily diacyglycerols and triacyglycerols). Of these, four were associated with risk of incident T2D and mediated ∼12% of the progression from GDM to T2D. The identified lipid species modestly improved the predictive performance for incident T2D above classical risk factors when the entire follow-up period was considered.
CONCLUSIONS
GDM was associated with a wide range of lipid metabolic alterations at early postpartum, among which some lipid species were also associated with incident T2D and mediated the progression from GDM to T2D. The improvements attained by including lipid species in the prediction of T2D provides new insights regarding the early detection and prevention of progression to T2D.
Topics: Infant; Pregnancy; Female; Humans; Adult; Male; Diabetes, Gestational; Diabetes Mellitus, Type 2; Lipidomics; Prospective Studies; Phosphatidylcholines; Postpartum Period
PubMed: 37043831
DOI: 10.2337/dc22-1841 -
Research (Washington, D.C.) 2023Localized intestine inflammation could induce short-term increases in colonic oxygenation and leads to increases in the aerobic bacteria population and reduction in the...
Localized intestine inflammation could induce short-term increases in colonic oxygenation and leads to increases in the aerobic bacteria population and reduction in the anaerobic bacteria population by changing the intestinal environment. However, the mechanisms involved and the associated functions of intestinal anaerobes in gut health still remain unclear. Here, we found that early-life depletion of gut microbiota exacerbated later colitis, while mid-life microbiota depletion showed partially reduced colitis. Notably, we observed that early-life gut microbiota depletion confers susceptibility to ferroptosis in colitis. In contrast, restitution of early-life microbiota conferred protection against colitis and inhibited ferroptosis triggered by gut microbiota dysbiosis. Similarly, colonization with anaerobic microbiota from young mice suppressed colitis. These results may attribute to high abundance of plasmalogen-positive (plasmalogen synthase [PlsA/R]-positive) anaerobes and plasmalogens (one of the common ether lipids) in young mice but reduced abundance in the development of inflammatory bowel disease. Early-life anaerobic bacteria elimination also resulted in the aggravation of colitis, while this aggravation phenotype was reverted by plasmalogen administration. Interestingly, plasmalogens inhibited ferroptosis triggered by microbiota dysbiosis. We further find that the alkenyl-ether group of plasmalogens was critical to colitis prevention and ferroptosis inhibition. These data point to one of the mechanisms by which the gut microbiota controls susceptibility to colitis and ferroptosis early in life via microbial-derived ether lipids.
PubMed: 37040489
DOI: 10.34133/research.0037 -
Advanced Science (Weinheim,... Jun 2023Meat is among the most consumed foods worldwide and has a unique flavor and high nutrient density in the human diet. However, the genetic and biochemical bases of meat...
Meat is among the most consumed foods worldwide and has a unique flavor and high nutrient density in the human diet. However, the genetic and biochemical bases of meat nutrition and flavor are poorly understood. Here, 3431 metabolites and 702 volatiles in 423 skeletal muscle samples are profiled from a gradient consanguinity segregating population generated by Pekin duck × Liancheng duck crosses using metabolomic approaches. The authors identified 2862 metabolome-based genome-wide association studies (mGWAS) signals and 48 candidate genes potentially modulating metabolite and volatile levels, 79.2% of which are regulated by cis-regulatory elements. The level of plasmalogen is significantly associated with TMEM189 encoding plasmanylethanolamine desaturase 1. The levels of 2-pyrrolidone and glycerophospholipids are regulated by the gene expression of AOX1 and ACBD5, which further affects the levels of volatiles, 2-pyrrolidone and decanal, respectively. Genetic variations in GADL1 and CARNMT2 determine the levels of 49 metabolites including L-carnosine and anserine. This study provides novel insights into the genetic and biochemical basis of skeletal muscle metabolism and constitutes a valuable resource for the precise improvement of meat nutrition and flavor.
Topics: Animals; Humans; Genome-Wide Association Study; Ducks; Meat; Metabolome; Muscle, Skeletal; Carboxy-Lyases
PubMed: 37013465
DOI: 10.1002/advs.202300148 -
Physiological Genomics May 2023Sex differences in energy metabolism during acute, submaximal exercise are well documented. Whether these sex differences influence metabolic and physiological responses...
Sex differences in energy metabolism during acute, submaximal exercise are well documented. Whether these sex differences influence metabolic and physiological responses to sustained, physically demanding activities is not well characterized. This study aimed to identify sex differences within changes in the serum metabolome in relation to changes in body composition, physical performance, and circulating markers of endocrine and metabolic status during a 17-day military training exercise. Blood was collected, and body composition and lower body power were measured before and after the training on 72 cadets (18 women). Total daily energy expenditure (TDEE) was assessed using doubly labeled water in a subset throughout. TDEE was greater in men (4,085 ± 482 kcal/d) than in women (2,982 ± 472 kcal/d, < 0.001), but not after adjustment for dry lean mass (DLM). Men tended to lose more DLM than women (mean change [95% CI]: -0.2[-0.3, -0.1] vs. -0.0[-0.0, 0.0] kg, = 0.063, Cohen's = 0.50) and have greater reductions in lower body power (-244[-314, -174] vs. -130[-209, -51] W, = 0.085, = 0.49). Reductions in DLM and lower body power were correlated ( = 0.325, = 0.006). Women demonstrated greater fat oxidation than men (Δfat mass/DLM: -0.20[-0.24, -0.17] vs. -0.15[-0.17, -0.13] kg, = 0.012, = 0.64). Metabolites within pathways of fatty acid, endocannabinoid, lysophospholipid, phosphatidylcholine, phosphatidylethanolamine, and plasmalogen metabolism increased in women relative to men. Independent of sex, changes in metabolites related to lipid metabolism were inversely associated with changes in body mass and positively associated with changes in endocrine and metabolic status. These data suggest that during sustained military training, women preferentially mobilize fat stores compared with men, which may be beneficial for mitigating loss of lean mass and lower body power. Women preferentially mobilize fat stores compared with men in response to sustained, physically demanding military training, as evidenced by increased lipid metabolites and enhanced fat oxidation, which may be beneficial for mitigating loss of lean mass and lower body power.
Topics: Humans; Female; Male; Sex Characteristics; Body Composition; Exercise; Oxidation-Reduction; Energy Metabolism; Metabolome
PubMed: 37012051
DOI: 10.1152/physiolgenomics.00180.2022 -
Journal of Physiology and Biochemistry May 2023The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the...
The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the Prevención con Dieta Mediterránea (PREDIMED) trial participants and incidence of AF. We conducted a nested case-control study (512 incident centrally adjudicated AF cases and 735 controls matched by age, sex, and center). Baseline plasma lipids were profiled using a Nexera X2 U-HPLC system coupled to an Exactive Plus orbitrap mass spectrometer. We estimated the association between 216 individual lipids and AF using multivariable conditional logistic regression and adjusted the p values for multiple testing. We also examined the joint association of lipid clusters with AF incidence. Hitherto, we estimated the lipidomics network, used machine learning to select important network-clusters and AF-predictive lipid patterns, and summarized the joint association of these lipid patterns weighted scores. Finally, we addressed the possible interaction by the randomized dietary intervention.Forty-one individual lipids were associated with AF at the nominal level (p < 0.05), but no longer after adjustment for multiple-testing. However, the network-based score identified with a robust data-driven lipid network showed a multivariable-adjusted OR of 1.32 (95% confidence interval: 1.16-1.51; p < 0.001). The score included PC plasmalogens and PE plasmalogens, palmitoyl-EA, cholesterol, CE 16:0, PC 36:4;O, and TG 53:3. No interaction with the dietary intervention was found. A multilipid score, primarily made up of plasmalogens, was associated with an increased risk of AF. Future studies are needed to get further insights into the lipidome role on AF.Current Controlled Trials number, ISRCTN35739639.
Topics: Humans; Atrial Fibrillation; Lipidomics; Risk Factors; Case-Control Studies; Plasmalogens
PubMed: 37004634
DOI: 10.1007/s13105-023-00958-0 -
Journal of Lipid Research May 2023Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the...
Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyceronephosphate O-acyltransferase, which has a strict substrate specificity reacting only with the long-chain acyl-CoAs. The aim of this study was to determine the origin of these long-chain acyl-CoAs. To this end, we developed a sensitive method for the measurement of de novo ether phospholipid synthesis in cells and, by CRISPR-Cas9 genome editing, generated a series of HeLa cell lines with deficiencies of proteins involved in peroxisomal biogenesis, beta-oxidation, ether lipid synthesis, or metabolite transport. Our results show that the long-chain acyl-CoAs required for the first step of ether lipid synthesis can be imported from the cytosol by the peroxisomal ABCD proteins, in particular ABCD3. Furthermore, we show that these acyl-CoAs can be produced intraperoxisomally by chain shortening of CoA esters of very long-chain fatty acids via beta-oxidation. Our results demonstrate that peroxisomal beta-oxidation and ether lipid synthesis are intimately connected and that the peroxisomal ABC transporters play a crucial role in de novo ether lipid synthesis.
Topics: Humans; Plasmalogens; HeLa Cells; Fatty Acids; Peroxisomes; Oxidation-Reduction; Acyl Coenzyme A; Ethers
PubMed: 36990386
DOI: 10.1016/j.jlr.2023.100364 -
Metabolites Feb 2023There has been increasing interest in bacterial lipids in recent years due, in part, to their emerging role as molecular signalling molecules. is an important member of...
There has been increasing interest in bacterial lipids in recent years due, in part, to their emerging role as molecular signalling molecules. is an important member of the mammalian gut microbiota that has been shown to produce sphingolipids (SP) that pass through the gut epithelial barrier to impact host SP metabolism and signal into host inflammation pathways. also produces a novel family of N-acyl amines (called glycine lipids) that are potent ligands of host Toll-like receptor 2 (TLR2). Here, we specifically examine the lipid signatures of four species of gut-associated . In total we identify 170 different lipids, and we report that the range and diversity of lipids is species specific. Multivariate analysis reveals that the differences in the lipid signatures are largely driven by the presence and absence of plasmalogens, glycerophosphoinositols and certain SP. Moreover, we show that, in , mutations altering either SP or glycine lipid biosynthesis result in significant changes in the levels of other lipids, suggesting the existence of a compensatory mechanisms required to maintain the functionality of the bacterial membrane.
PubMed: 36984802
DOI: 10.3390/metabo13030360 -
International Journal of Molecular... Mar 2023Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune... (Review)
Review
Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.
Topics: Animals; Alzheimer Disease; Lipopolysaccharides; Neuroinflammatory Diseases; Oxidative Stress; Inflammation; Cognitive Dysfunction; Diet; Models, Animal; Disease Models, Animal
PubMed: 36982996
DOI: 10.3390/ijms24065921 -
Journal of the American Chemical Society Apr 2023Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms...
Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms are largely unknown. As part of a project to identify immunomodulators produced by gut microbes, we analyzed the metabolome of , an actinomycete that figures prominently in numerous association studies. The associations are typically positive correlations of with pro-inflammatory responses and undesirable outcomes, but an association with favorable responses to PD-1/PD-L1 cancer immunotherapy is a notable exception. A phenotypic assay-guided screen using dendritic cells (mBMDCs) and cytokine readouts identified the active compound, which was structurally characterized as a lysoglycoglycerolipid with an acetal-bearing β-galactofuranose head group (CaLGL-1, ). The structural assignment was confirmed through total synthesis. Assays with , , and wt mBMDCs revealed TLR2-dependent signaling. CaLGL-1 is produced by a conversion of a bacterially biosynthesized plasmalogen (CaPlsM, ) to CaLGL-1 () in a low-pH environment.
Topics: Humans; Actinobacteria; Hydrogen-Ion Concentration; Lipids; Microbiota; Toll-Like Receptor 2; Dendritic Cells
PubMed: 36952265
DOI: 10.1021/jacs.3c00250 -
Microbiology (Reading, England) Mar 2023Bacteria produce an array of diverse, dynamic and often complex lipid structures, some of which function beyond their typical role in membrane structure. The model... (Review)
Review
Bacteria produce an array of diverse, dynamic and often complex lipid structures, some of which function beyond their typical role in membrane structure. The model organism, , has three major membrane lipids, which are glycerophosphoglycerol (phosphatidylglycerol), glycerophosphoethanolamine (phosphatidylethanolamine) and cardiolipin. However, it is now appreciated that some bacteria have the capacity to synthesize a range of lipids, including glycerophosphocholines, glycerophosphoinositols, 'phosphorous-free' -acyl amines, sphingolipids and plasmalogens. In recent years, some of these bacterial lipids have emerged as influential contributors to the microbe-host molecular dialogue. This review outlines our current knowledge of bacterial lipid diversity, with a focus on the membrane lipids of microbiome-associated bacteria that have documented roles as signalling molecules.
Topics: Membrane Lipids; Escherichia coli; Gastrointestinal Microbiome; Cardiolipins
PubMed: 36952261
DOI: 10.1099/mic.0.001315