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The Chinese indigenous Shiqi (SQ) pigeon and the imported White King (WK) pigeon are two meat-type pigeon breeds of economical and nutritional importance in China. They displayed significant differences in such meat quality traits as intramuscular fat (IMF) content and fatty acid (FA) compositions in the breast muscles. In this study, we aimed to screen candidate genes that could affect fat-related meat quality traits in meat-type pigeons. We investigated the polymorphic variations at the genomic level using double-digest restriction-associated DNA (ddRAD) sequencing in 12 squabs of SQ and WK pigeons that exhibited significant inter-breed differences in IMF content as well as FA and amino acid compositions in the breast muscles, and screened candidate genes influencing fat-related traits in squabs through gene ontology analysis and pathway analysis. By focusing on 6019 SNPs, which were located in genes with correct annotations and had the potential to induce changes in the encoded proteins, we identified 19 genes ( Show less

Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the impacts of BCFAs inferred from yak ghee on the expression of qualities related to lipid metabolism, natural pathways, and intestinal microbiota in mice. The treatment group (purified BCFAs from yak ghee) exhibited a decrease in cholesterol levels; a decrease in Show less

Flaxseed contains huge quantities of anti-nutritional factors (ANFs), which reduce the performance of livestock. Three different protease and multi-carbohydrase enzymes were included in wheat-flaxseed diets (WFD) and corn-flaxseed diets (CFD) to compare their effects on performance, egg n-3 deposition, and fatty acid transporter genes in laying hens. A total of 540, twenty-week-old, Nongda-3 laying hens (DW brown × Hy-line white) were randomly assigned to six dietary groups, including 10% WFD or 10% CFD plus (i) supplemental enzyme A (alkaline protease 40,000 and neutral protease 10,000 (U/g)), (ii) enzyme B (alkaline protease 40,000, neutral protease 10,000, and cellulase 4000 (U/g)), or iii) enzyme C (neutral protease 10,000, xylanase 35,000, β-mannanase 1500, β-glucanase 2000, cellulose 500, amylase 100, and pectinase 10,000 (U/g)). An interaction ( Show less

Foetal akinesia deformation sequence (FADS) represents a group of disorders resulting from absent or diminished in utero foetal mobility. The aetiology is multifactorial, including genetic, environmental, maternal, and foetal causes. The absence of foetal movements leading to multiple joint contractures, pulmonary hypoplasia, and intrauterine growth restriction are the key features of foetal akinesia deformation sequence. Herein we describe the case of a 30-year-old gravida 4 (para 2+1) who came for foetal ultrasound at 28 weeks of gestation due to decreased foetal movements. Ultrasound showed features of FADS with fixed flexed position of foetal limbs, pulmonary hypoplasia, polyhydramnios, and intrauterine growth restriction. The timely use of ultrasound enables early detection of these cases and aids in appropriate counselling and management. Show less

Fetal arthrogryposis is a well-recognised ultrasonographic phenotype, caused by both genetic, maternal and extrinsic factors. When present with fetal growth restriction, pulmonary hypoplasia and multiple joint contractures, it is often referred to as fetal akinesia deformation sequence (FADS). Historically, elucidating genetic causes of arthryogryposis/FADS has been challenging; there are now more than 150 genes known to cause arthrogryposis through myopathic, neuromuscular and metabolic pathways affecting fetal movement. FADS is associated with over 400 medical conditions making prenatal diagnosis challenging. Here we present a case of FADS diagnosed at 19 weeks gestation with progression to severe fetal hydrops and stillbirth at 26-weeks gestation. Initial investigations including combined first trimester screening, TORCH (infection) screen and chromosomal microarray were normal. Trio whole exome sequencing (WES) detected compound heterozygous likely pathogenic CACNA1S gene variants associated with autosomal dominant (AD) and autosomal recessive (AR) congenital myopathy and FADS. To our knowledge, this is the first prenatal diagnosis of this condition. Show less

Most current metabolomics studies of oral squamous cell carcinoma (OSCC) are mainly focused on identifying potential biomarkers for early screening and diagnosis, while few studies have investigated the metabolic profiles promoting metastasis. In this study, we aimed to explore the altered metabolic pathways associated with metastasis of OSCC. Here, we identified four OSCC cell models (CAL27, HN6, HSC-3, SAS) that possess different invasive heterogeneity via the transwell invasion assay and divided them into high-invasive (HN6, SAS) and low-invasive (CAL27, HSC-3) cells. Quantitative analysis and stable isotope tracing using [U- Show less

Circulating fatty acids (FA) have an endogenous or exogenous origin and are metabolized under the effect of many enzymes. They play crucial roles in many mechanisms: cell signaling, modulation of gene expression, etc., which leads to the hypothesis that their perturbation could be the cause of disease development. FA in erythrocytes and plasma rather than dietary FA could be used as a biomarker for many diseases. Cardiovascular disease was associated with elevated trans FA and decreased DHA and EPA. Increased arachidonic acid and decreased Docosahexaenoic Acids (DHA) were associated with Alzheimer's disease. Low Arachidonic acid and DHA are associated with neonatal morbidities and mortality. Decreased saturated fatty acids (SFA), increased monounsaturated FA (MUFA) and polyunsaturated FA (PUFA) (C18:2 n-6 and C20:3 n-6) are associated with cancer. Additionally, genetic polymorphisms in genes coding for enzymes implicated in FA metabolism are associated with disease development. FA desaturase (FADS1 and FADS2) polymorphisms are associated with Alzheimer's disease, Acute Coronary Syndrome, Autism spectrum disorder and obesity. Polymorphisms in FA elongase (ELOVL2) are associated with Alzheimer's disease, Autism spectrum disorder and obesity. FA-binding protein polymorphism is associated with dyslipidemia, type 2 diabetes, metabolic syndrome, obesity, hypertension, non-alcoholic fatty liver disease, peripheral atherosclerosis combined with type 2 diabetes and polycystic ovary syndrome. Acetyl-coenzyme A carboxylase polymorphisms are associated with diabetes, obesity and diabetic nephropathy. FA profile and genetic variants of proteins implicated in FA metabolism could be considered as disease biomarkers and may help with the prevention and management of diseases. Show less

Dysregulation of fatty acid metabolism and de novo lipogenesis is a key driver of several cancer types through highly unsaturated fatty acid (HUFA) signaling precursors such as arachidonic acid. The human chromosome 11q13 locus has long been established as the most frequently amplified in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) responsible for HUFA biosynthesis localize to the 11q12-13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus potentially driving various cancer types. FADS2 silencing causes synthesis of sciadonic acid (5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to arachidonic acid (5Z,8Z,11Z,14Z-20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Palmitic acid has substrate specificity for both SCD and FADS2. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity and sapienic acid biosynthesis. Elevated serum mead acid levels found in hepatocellular carcinoma patients suggest an unsatisfied demand for arachidonic acid. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. FADS2 circular RNAs are associated with shorter overall survival in colorectal cancer patients. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders. Show less

Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity in the Chinese indigenous Qingyuan partridge chicken. A cohort of 180 healthy 119-day-old chickens was subjected to a randomized assignment into three groups, identified as the control, R200, and R400 groups, with respective supplementation of 0, 200, and 400 mg/kg of rutin. The results revealed insignificance in growth performance, namely, average daily gain, average daily feed intake, and feed-to-gain ratio, across the various treatment groups ( Show less

Lipid metabolism differs significantly between grazing and stall-feeding lambs, affecting the quality of livestock products. As two critical organs of lipid metabolism, the differences between feeding patterns on rumen and liver metabolism remain unclear. In this study, 16S rRNA, metagenomics, transcriptomics, and untargeted metabolomics were utilized to investigate the key rumen microorganisms and metabolites, as well as liver genes and metabolites associated with fatty acid metabolism under indoor feeding (F) and grazing (G). Compared with grazing, indoor feeding increased ruminal propionate content. Using metagenome sequencing in combination with 16S rRNA amplicon sequencing, the results showed that the abundance of propionate-producing Succiniclasticum and hydrogenating bacteria Tenericutes was enriched in the F group. For rumen metabolism, grazing caused up-regulation of EPA, DHA and oleic acid and down-regulation of decanoic acid, as well as, screening for 2-ketobutyric acid as a vital differential metabolite, which was enriched in the propionate metabolism pathway. In the liver, indoor feeding increased 3-hydroxypropanoate and citric acid content, causing changes in propionate metabolism and citrate cycle, while decreasing the ETA content. Then, the liver transcriptome revealed that 11 lipid-related genes were differentially expressed in the two feeding patterns. Correlation analysis showed that the expression of CYP4A6, FADS1, FADS2, ALDH6A1 and CYP2C23 was significantly associated with the propionate metabolism process, suggesting that propionate metabolism may be an important factor mediating the hepatic lipid metabolism. Besides, the unsaturated fatty acids in muscle, rumen and liver also had a close correlation. Overall, our data demonstrated that rumen microbial-driven metabolite from grazing lambs potentially regulates multiple hepatic lipid-related genes, ultimately affecting body fatty acid metabolism. Show less

The aim of this study was to identify differentially expressed genes, biological processes, and metabolic pathways related to adipogenesis and lipogenesis in calves receiving different diets during the cow-calf phase. Forty-eight uncastrated F1 Angus × Nellore males were randomly assigned to two treatments from thirty days of age to weaning: no creep feeding (G1) or creep feeding (G2). The creep feed offered contained ground corn (44.8%), soybean meal (40.4%), and mineral core (14.8%), with 22% crude protein and 65% total digestible nutrients in dry matter. After weaning, the animals were feedlot finished for 180 days and fed a single diet containing 12.6% forage and 87.4% corn-based concentrate. Show less

Daily exposure to bisphenols can affect reproductive functions due to their pseudo-estrogenic and/or anti-androgenic effects. Testicular lipids contain high levels of polyunsaturated fatty acids necessary for sperm maturity, motility, and spermatogenesis. Whether prenatal exposure to bisphenols alters testicular fatty acid metabolism in adult offspring is unknown. Pregnant Wistar rats were gavaged from gestational day 4 to 21 with BPA and BPS (0.0, 0.4, 4.0, 40.0 μg/kg bw/day). Despite increased body and testis weight, the total testicular cholesterol, triglyceride, and plasma fatty acids were unaffected in the offspring. Lipogenesis was upregulated by increased SCD-1, SCD-2, and expression of lipid storage (ADRP) and trafficking protein (FABP4). The arachidonic acid, 20:4 n-6 (ARA) and docosapentaenoic acid, 22:5 n-6 (DPA) levels were decreased in the BPA-exposed testis, while BPS exposure had no effects. The expression of PPARα, PPARγ proteins, and CATSPER2 mRNA were decreased, which are important for energy dissipation and the motility of the sperm in the testis. The endogenous conversion of linoleic acid,18:2 n-6 (LA), to ARA was impaired by a reduced ARA/LA ratio and decreased FADS1 expression in BPA-exposed testis. Collectively, fetal BPA exposure affected endogenous long-chain fatty acid metabolism and steroidogenesis in the adult testis, which might dysregulate sperm maturation and quality. Show less

Membrane fatty acid desaturase (FADS)-like superfamily proteins (FADSs) are essential for the synthesis of unsaturated fatty acids (UFAs). Recently, studies on FADS in fishes have mostly focused on marine species, and a comprehensive analysis of the FADS superfamily, including the FADS, stearoyl-CoA desaturase (SCD), and sphingolipid delta 4-desaturase (DEGS) families, in freshwater economic fishes is urgently required. To this end, we conducted a thorough analysis of the number, gene/protein structure, chromosomal location, gene linkage map, phylogeny, and expression of the FADS superfamily. We identified 156 FADSs genes in the genome of 27 representative species. Notably, FADS1 and SCD5 were lost in most freshwater fish and other teleosts. All FADSs proteins contain 4 transmembrane helices and 2-3 amphipathic α-helices. FADSs in the same family are often linked on the same chromosome; moreover, FADS and SCD or DEGS are frequently collocated on the same chromosome. In addition, FADS, SCD, and DEGS family proteins share similar evolutionary patterns. Interestingly, FADS6, as a member of the FADS family, exhibits a similar gene structure and chromosome location to that of SCD family members, which may be the transitional form of FADS and SCD. This study shed light on the type, structure, and phylogenetic relationship of FADSs in freshwater fishes, offering a new perspective into the functional mechanism analysis of FADSs. Show less

Intrauterine development is a key period in human life. The foetal progress largely depends on the function of the placenta, whose responsibility is transportation and biosynthesis of fatty acids. Desaturation enzymes play a key role in placental fatty acid metabolism. Expression of genes coding for desaturases may be associated with pregnancy abnormalities. The objective of this study was to determine the transcriptional activity of the placental genes Fatty Acid Desaturases 1, 2 and 3 (FADS 1, 2 and 3) in women who gave birth to the infants appropriate for gestational age, large for gestational age, small for gestational age, with intrauterine growth restriction and born preterm. 34 pregnant women aged 21-37 years old participated in the study. The placental samples were taken from a site located 2-3 cm away from the umbilical cord attachment. The collected tissue sections were stored in RNAlater according to the manufacturer's protocol, until required for molecular analysis. The expression profiles of FADS1, FADS2 and FADS3 were determined with RT-qPCR. There was no difference in FADS1 and FADS2 expression between the groups. However, the differences in the expression of the FADS3 were found. Analysis of the FADS1, FADS2 and FADS3 transcription showed significant differences between most of the examined groups. Our findings suggest that the transcriptional activity of FADS genes changes with the severity of intrauterine disorders and is associated with foetal lipid disorders linked to a greater accumulation of fat in the foetal tissues. Show less

Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90-111 years old, n = 49) from Sicily was compared to adults (18-64 years old, n = 69) and older adults (65-89 years old, n = 54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the levels of saturated FA (SFA) remained unchanged. Interestingly, distinctively higher circulatory levels of monounsaturated FA (MUFA) in LLIs compared to adults and older adults were observed. In addition, among LLIs, rs174537 in the FA desaturase 1/2 (FADS1/2) gene was associated with linoleic acid (LA, 18:2n-6) and docosatetraenoic acid (DTA, 22:4n-6) levels, and the rs953413 in the elongase of very long FA 2 (ELOVL2) was associated with DTA levels. We further observed that rs174579 and rs174626 genotypes in FADS1/2 significantly affect delta-6 desaturase (D6D) activity. In conclusion, our results suggest that the LLIs have a different FA profile characterized by high MUFA content, which indicates reduced peroxidation while maintaining membrane fluidity. Show less

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success. Show less

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD. Show less

Glioblastoma multiforme (GBM) is one of the most aggressive gliomas. New and more effective therapeutic approaches are being sought based on studies of the various mechanisms of GBM tumorigenesis, including the synthesis and metabolism of arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA). PubMed, GEPIA, and the transcriptomics analysis carried out by Seifert et al. were used in writing this paper. In this paper, we discuss in detail the biosynthesis of this acid in GBM tumors, with a special focus on certain enzymes: fatty acid desaturase (FADS)1, FADS2, and elongation of long-chain fatty acids family member 5 (ELOVL5). We also discuss ARA metabolism, particularly its release from cell membrane phospholipids by phospholipase A Show less

Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in asthma patients, whereas the effects of fatty acids on the actual risk of asthma remain controversial. This study comprehensively investigated the causal effects of serum fatty acids on asthma risk using two-sample bidirectional Mendelian Randomization (MR) analysis. Genetic variants strongly associated with 123 circulating fatty acid metabolites were extracted as instrumental variables, and a large GWAS data of asthma was used to test effects of the metabolites on this outcome. The inverse-variance weighted method was used for primary MR analysis. The weighted median, MR-Egger regression, MR-PRESSO, and leave-one-out analyses were utilized to evaluate heterogeneity and pleiotropy. Potential confounders were adjusted by performing multivariable MR analyses. Reverse MR analysis was also conducted to estimate the causal effect of asthma on candidate fatty acid metabolites. Further, we performed colocalization analysis to examine the pleiotropy of variants within the fatty acid desaturase 1 (FADS1) locus between the significant metabolite traits and the risk of asthma. Cis-eQTL-MR and colocalization analysis were also performed to determine the association between RNA expression of FADS1 and asthma. Genetically instrumented higher average number of methylene groups was causally associated with a lower risk of asthma in primary MR analysis, while inversely, the higher ratio of bis-allylic groups to double bonds and the higher ratio of bis-allylic groups to total fatty acids, were associated with higher probabilities of asthma. Consistent results were obtained in multivariable MR when adjusted for potential confounders. However, these effects were completely eliminated after SNPs correlated with the FADS1 gene were excluded. The reverse MR also found no causal association. The colocalization analysis suggested that the three candidate metabolite traits and asthma likely share causal variants within the FADS1 locus. In addition, the cis-eQTL-MR and colocalization analyses demonstrated a causal association and shared causal variants between FADS1 expression and asthma. Our study supports a negative association between several PUFA traits and the risk of asthma. However, this association is largely attributed to the influence of FADS1 polymorphisms. The results of this MR study should be carefully interpreted given the pleiotropy of SNPs associated with FADS1. Show less

Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN. Show less

Fatty acid desaturase (FADS) genetic polymorphisms are strongly correlated with the risk of dyslipidemia and cardiovascular disease. In this study, we examined the impact of FADS1 and FADS2 genetic variants on plasma lipid status, and assessed interactions between FADS genetic polymorphisms and plasma n-3/n-6 fatty acids regarding lipid status within a population of 816 Taiwanese patients with type 2 diabetes. Selected tag single-nucleotide polymorphisms (FADS1 rs174546 [T/C]; FADS2 rs174602 [A/G] and rs2072114 [A/G]) were genotyped (n = 816). The distribution of genotypes were compared with reports publicly available in the Genome Aggregation Database for East Asian populations (https://gnomad.broadinstitute.org). In the subgroup of patients not taking lipid-lowering medications (n = 192), we observed that the G allele of FADS2 rs174602 was statistically significantly correlated with lower low-density lipoprotein cholesterol (LDL-C) concentrations (P = 0.001), whereas the G allele of rs2072114 was marginally associated with LDL-C concentrations (P = 0.091). Using a general linear model adjusted for confounding factors, statistically significant interactions (P = 0.016) between single-nucleotide polymorphisms in rs2072114 and a low alpha-linolenic acid (18:3n-3)/linoleic acid (18:2n-6) ratio; the G allele correlated with lower LDL-C levels among individuals with a low alpha-linolenic acid/linoleic acid ratio. Interaction between rs174602 single-nucleotide polymorphisms and low alpha-linolenic acid/linoleic acid values on LDL-C was only marginally significant (P = 0.063). Our results show the role of n-3/n-6 dietary polyunsaturated fatty acids in modifying the effects of genetic susceptibility on lipoprotein concentrations in patients with type 2 diabetes. Our findings highlight the potential of interventions with dietary polyunsaturated fatty acids regarding developing individualized prevention strategies for type 2 diabetes presenting with co-occurring dyslipidemia and cardiovascular diseases. Show less

The role of Zn in human health was discovered 60 years ago, and despite remarkable research efforts, a sufficiently sensitive and specific biomarker of Zn status is still lacking. Plasma/serum Zn, currently the best available and most accepted population Zn status indicator, responds well to severe Zn deficiency, yet, mild to moderate Zn deficiency states usually remain unrecognized. Identifying early-stage Zn deficiency requires additional robust markers of Zn status. This paper discusses the sensitivity, specificity, and responsiveness of plasma Zn concentrations to Zn interventions. It describes the biochemical and dietary basis for the causal association between Zn and fatty acid desaturases activity, FADS1 and FADS2, based on data collected through studies performed in animals and/or humans. The influence of potential confounders and covariates on the observed relationships is considered. Additional potential Zn biomarkers are discussed and suggestions for further research in this area are provided. Show less

Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at Show less

Stem cells are defined by their ability to self-renew and differentiate, both shown in multiple studies to be regulated by metabolic processes. To decipher metabolic signatures of self-renewal in blastocyst-derived stem cells, we compared early differentiating embryonic stem cells (ESCs) and their extra-embryonic counterparts, trophoblast (T)SCs to their self-renewing counterparts. A metabolomics analysis pointed to the desaturation of fatty acyl chains as a metabolic signature of differentiating blastocyst-derived SCs via the upregulation of delta-6 desaturase (D6D; FADS2) and delta-5 desaturase (D5D; FADS1), key enzymes in the biosynthesis of polyunsaturated fatty acids (PUFAs). The inhibition of D6D or D5D by specific inhibitors or SiRNA retained stemness in ESCs and TSCs, and attenuated endoplasmic reticulum (ER) stress-related apoptosis. D6D inhibition in ESCs upregulated stearoyl-CoA desaturase-1 (Scd1), essential to maintain ER homeostasis. In TSCs, however, D6D inhibition downregulated Scd1. TSCs show higher Scd1 mRNA expression and high levels of monounsaturated fatty acyl chain products in comparison to ESCs. The addition of oleic acid, the product of Scd1 (essential for ESCs), to culture medium, was detrimental to TSCs. Interestingly, TSCs express a high molecular mass variant of Scd1 protein, hardly expressed by ESCs. Taken together, our data suggest that lipid desaturation is a metabolic regulator of the balance between differentiation and self-renewal of ESCs and TSCs. They point to lipid polydesaturation as a driver of differentiation in both cell types. Monounsaturated fatty acids (MUFAs), essential for ESCs are detrimental to TSCs. Show less

A better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy aging. Here, we compared the gut microbiome and blood metabolome of extremely long-lived individuals (94-105 years old) to that of their children (50-79 years old) in 116 Han Chinese families. We found extensive metagenomic and metabolomic remodeling in advanced age and observed a generational divergence in the correlations with socioeconomic factors. An analysis of quantitative trait loci revealed that genetic associations with metagenomic and metabolomic features were largely generation-specific, but we also found 131 plasma metabolic quantitative trait loci associations that were cross-generational with the genetic variants concentrated in six loci. These included associations between FADS1/2 and arachidonate, PTPA and succinylcarnitine and FLVCR1 and choline. Our characterization of the extensive metagenomic and metabolomic remodeling that occurs in people reaching extreme ages may offer new targets for aging-related interventions. Show less

Childhood obesity is associated with adult obesity, which is a risk factor for chronic diseases. Obesity, as an environmental cue, alters circadian rhythms. The hypothesis of this study was that consumption of a high-fat diet alters metabolic rhythms in pubertal mice. Weanling female C57BL/6NHsd mice were fed a standard AIN93G diet or a high-fat diet (HFD) for 3 weeks. Livers were collected from six-week-old mice every 4 h over a period of 48 h for transcriptome analysis. The HFD altered rhythmicity of differentially rhythmic transcripts in liver. Specifically, the HFD elevated expression of circadian genes Show less