Glu298Asp (rs1799983) Polymorphism Influences Postprandial Vascular Reactivity and the Insulin Response to Meals of Varying Fat Composition in Postmenopausal Women: Findings from the Randomized, Controlled Dietary Intervention and VAScular function (DIVAS)-2 Study.

BACKGROUND: Previous acute studies suggest the Glu298Asp polymorphism (rs1799983) may influence vascular reactivity in response to long-chain n-3 PUFA intake. However, the effects of this genotype on postprandial vascular function after meals rich in SFAs, n-6 PUFAs, and MUFAs are unclear. OBJECTIVES: This study determined the impact of the Glu298Asp polymorphism on changes in vascular function and cardiometabolic risk biomarkers in response to sequential meals of varying fat composition. METHODS: In a randomized, double-blind, crossover, acute study, 32 postmenopausal women (mean ± SD age: 58 ± 5 y; BMI: 25.9 ± 4.1 kg/m2) consumed mixed meals (breakfast: 0 min, 50 g fat; lunch: 330 min, 30 g fat) containing SFAs, n-6 PUFAs, or MUFAs on 3 occasions. Blood samples for cardiometabolic disease risk markers and real-time measures of vascular reactivity [including flow-mediated dilatation (FMD; primary outcome)] were collected/performed before and regularly for 480 min after breakfast. Participants were retrospectively genotyped for the Glu298Asp (rs1799983) polymorphism. Data were analyzed using linear mixed models. RESULTS: For the postprandial %FMD response, a test fat × genotype interaction was observed for the AUC (P = 0.019) but not incremental AUC (IAUC), with the AUC being ∼24% greater after MUFA- than after SFA- and n-6 PUFA-rich meals in the Glu298 homozygotes (P ≤ 0.026). Test fat × genotype interactions were also evident for postprandial insulin (P ≤ 0.005), with the MUFA-rich meals demonstrating significantly higher AUC (12.8%/14.9%), IAUC (14.6%/20.0%), and maximum concentration (20.0%/34.5%) than the SFA- and n-6 PUFA-rich meals, respectively, in Asp298 carriers (P < 0.05). Genotype did not influence other study outcome measures in response to the test fats. CONCLUSIONS: Our findings suggest the Glu298Asp polymorphism may represent a potential determinant of the inter-individual variability in postprandial responsiveness of %FMD and insulin to acute meal fat composition in postmenopausal women. Further studies are required to confirm these observations.This trial was registered at clinicaltrials.gov as NCT02144454.

Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver.

Hepatic circadian gene transcription is tightly coupled to feeding behavior, which has a profound impact on metabolic disorders associated with diet-induced obesity. Here, we describe a genomics approach to uncover mechanisms controlling hepatic postprandial gene expression. Combined transcriptomic and cistromic analysis identified hundreds of circadian-regulated genes and enhancers controlled by feeding. Postprandial suppression of enhancer activity was associated with reduced glucocorticoid receptor (GR) and Forkhead box O1 (FOXO1) occupancy of chromatin correlating with reduced serum corticosterone levels and increased serum insulin levels. Despite substantial co-occupancy of feeding-regulated enhancers by GR and FOXO1, selective disruption of corticosteroid and/or insulin signaling resulted in dysregulation of specific postprandial regulated gene programs. In combination, these signaling pathways operate a major part of the genes suppressed by feeding. Importantly, the feeding response was disrupted in diet-induced obese animals, which was associated with dysregulation of several corticosteroid- and insulin-regulated genes, providing mechanistic insights to dysregulated circadian gene transcription associated with obesity.

Modulation of Drosophila post-feeding physiology and behavior by the neuropeptide leucokinin.

Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood. As a first step towards understanding these mechanisms, we delineated LK circuitry that governs various aspects of post-feeding physiology and behavior. We found that impaired LK signaling in Lk and Lk receptor (Lkr) mutants affects diverse but coordinated processes, including regulation of stress, water homeostasis, feeding, locomotor activity, and metabolic rate. Next, we sought to define the populations of LK neurons that contribute to the different aspects of this physiology. We find that the calcium activity in abdominal ganglia LK neurons (ABLKs), but not in the two sets of brain neurons, increases specifically following water consumption, suggesting that ABLKs regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of Lkr expression, mined a brain single-cell transcriptome dataset for genes coexpressed with Lkr, and identified synaptic partners of LK neurons. Lkr expression in the brain insulin-producing cells (IPCs), gut, renal tubules and chemosensory cells, correlates well with regulatory roles detected in the Lk and Lkr mutants. Furthermore, these mutants and flies with targeted knockdown of Lkr in IPCs displayed altered expression of insulin-like peptides (DILPs) and transcripts in IPCs and increased starvation resistance. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons have different targets, but modulate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating feeding-related neuroendocrine regulation of vital behavior and physiology.

Free Fatty Acid-Induced Peptide YY Expression Is Dependent on TG Synthesis Rate and Xbp1 Splicing.

Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of the systemic effects of these hormones, very little is known concerning the mechanisms by which nutrients, such as dietary fats, can promote the expression of genes involved in L-cell hormone production. We have tested the role of various dietary fats and found that after hydrolysis into free fatty acids (FFA's), there is a differential response in the extent to which they induce PYY gene and protein production. The effect of FFA's also seems to relate to triglyceride (TG) re-esterification rate, with MUFA re-esterifying faster with lower PYY production. We have also found that there are differences in potency of FFA's based on their desaturation patterns in vitro. The potency effect of FFA's is influenced by the rate of TG re-esterification, such that the longer FFA's are in contact with L-cells, the more PYY they produce. We found that chronic consumption of high-fat diets enables the small intestine to re-esterify FFA's into TG faster and earlier which resulted in a blunted postprandial PYY response. Lastly, we found that FFA's induce X-box-binding protein-1 activation (Xbp1s) in L-cells and that adenoviral delivery of Xbp1s was sufficient to induce PYY gene expression. Taken together, the present work indicates that dietary fat can induce satiety, in part, prior to re-esterification. Chronic high-fat diet consumption increases the rate of re-esterification which diminishes satiety and may lead to increased food intake. Targeting intestinal TG synthesis may prove beneficial in restoring obesity-associated reductions in postprandial satiety.

Profiling the rainbow trout hepatic miRNAome under diet-induced hyperglycemia.

Carnivorous rainbow trout exhibit prolonged postprandial hyperglycemia when fed a diet exceeding 20% carbohydrate content. This poor capacity to utilize carbohydrates has led to rainbow trout being classified as "glucose-intolerant" (GI). The metabolic phenotype has spurred research to identify the underlying cellular and molecular mechanisms of glucose intolerance, largely because carbohydrate-rich diets provide economic and ecological advantages over traditionally used fish meal, considered unsustainable for rainbow trout aquaculture operations. Evidence points to a contribution of hepatic intermediary carbohydrate and lipid metabolism, as well as upstream insulin signaling. Recently, microRNAs (miRNAs), small noncoding RNAs acting as negative posttranscriptional regulators affecting target mRNA stability and translation, have emerged as critical regulators of hepatic control of glucose-homeostasis in mammals, revealing that dysregulated hepatic miRNAs might play a role in organismal hyperglycemia in metabolic disease. To determine whether hepatic regulatory miRNA networks may contribute to GI in rainbow trout, we induced prolonged postprandial hyperglycemia in rainbow trout by using a carbohydrate-rich diet and profiled genome-wide hepatic miRNAs in hyperglycemic rainbow trout compared with fasted trout and trout fed a diet devoid of carbohydrates. Using small RNA next-generation sequencing and real-time RT-PCR validation, we identified differentially regulated hepatic miRNAs between these groups and used an in silico approach to predict bona fide mRNA targets and enriched pathways. Diet-induced hyperglycemia resulted in differential regulation of hepatic miRNAs compared with fasted fish. Some of the identified miRNAs, such as miRNA-27b-3p and miRNA-200a-3p, are known to be responsive to hyperglycemia in the liver of hyperglycemic glucose-tolerant fish and mammals, suggesting an evolutionary conserved regulation. Using Gene Ontology term-based enrichment analysis, we identify intermediate carbohydrate and lipid metabolism and insulin signaling as potential targets of posttranscriptional regulation by hyperglycemia-regulated miRNAs and provide correlative expression analysis of specific predicted miRNA-target pairs. This study identifies hepatic miRNAs in rainbow trout that exhibit differential postprandial expression in response to diets with different carbohydrate content and predicts posttranscriptionally regulated target mRNAs enriched for pathways involved in glucoregulation. Together, these results provide a framework for testable hypotheses of functional involvement of specific hepatic miRNAs in GI in rainbow trout.

Metabolomics Reveal Altered Postprandial Lipid Metabolism After a High-Carbohydrate Meal in Men at High Genetic Risk of Diabetes.

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene confers one of the strongest genetic predispositions to type 2 diabetes, but diabetes development can be modified by diet. OBJECTIVE: The aim of our study was to evaluate postprandial metabolic alterations in healthy men with a high genetic risk of diabetes, after two meals with varying macronutrient content. METHODS: The study was conducted in 21 homozygous nondiabetic men carrying the high-risk (HR, n = 8, age: 31.2 ± 6.3 y, body mass index (BMI, kg/m2) 28.5 ± 8.1) or low-risk (LR, n = 13, age: 35.2 ± 10.3 y, BMI: 28.1 ± 6.4) genotypes at the rs7901695 locus. During two meal challenge test visits subjects received standardized isocaloric (450 kcal) liquid meals: high-carbohydrate (HC, carbohydrates: 89% of energy) and normo-carbohydrate (NC, carbohydrates: 45% of energy). Fasting (0 min) and postprandial (30, 60, 120, 180 min) plasma samples were analyzed for metabolite profiles through untargeted metabolomics. Metabolic fingerprinting was performed on an ultra-high-performance liquid chromatography (UHPLC) system connected to an iFunnel quadrupole-time-of-flight (Q-TOF) mass spectrometer. RESULTS: In HR-genotype men, after the intake of an HC-meal, we noted a significantly lower area under the curves (AUCs) of postprandial plasma concentrations of most of the phospholipids (-37% to -53%, variable importance in the projection (VIP) = 1.2-1.5), lysophospholipids (-29% to -86%, VIP = 1.1-2.6), sphingolipids (-32% to -47%, VIP = 1.1-1.3), as well as arachidonic (-36%, VIP = 1.4) and oleic (-63%, VIP = 1.3) acids, their metabolites: keto- and hydoxy-fatty acids (-38% to -78%, VIP = 1.3-2.5), leukotrienes (-65% to -83%, VIP = 1.4-2.2), uric acid (-59%, VIP = 1.5), and pyroglutamic acid (-65%, VIP = 1.8). The AUCs of postprandial sphingosine concentrations were higher (125-832%, VIP = 1.9-3.2) after the NC-meal, AUCs of acylcarnitines were lower (-21% to -61%, VIP = 1.1-2.4), and AUCs of fatty acid amides were higher (51-508%, VIP = 1.7-3.1) after the intake of both meals. CONCLUSIONS: In nondiabetic men carrying the TCF7L2 HR genotype, subtle but detectable modifications in intermediate lipid metabolism are induced by an HC-meal. This trial was registered at www.clinicaltrials.gov as NCT03792685.

Green tea extract and catechol-O-methyltransferase genotype modify the post-prandial serum insulin response in a randomised trial of overweight and obese post-menopausal women.

BACKGROUND: Green tea extract (GTE) may be involved in a favourable post-prandial response to high-carbohydrate meals. The catechol-O-methyltransferase (COMT) genotype may modify these effects. We examined the acute effects of GTE supplementation on the post-prandial response to a high-carbohydrate meal by assessing appetite-associated hormones and glucose homeostasis marker concentrations in women who consumed 843 mg of (-)-epigallocatechin-3-gallate (EGCG) or placebo capsules for 11-12 months. METHODS: Sixty Caucasian post-menopausal women (body mass index ≥ 25.0 kg m-2 ) were included in a randomised, double-blind feeding study. GTE was consumed with a breakfast meal [2784.0 kJ (665.4 kcal); 67.2% carbohydrate]. Blood samples were drawn pre-meal, post-meal, and every 30 min for 4 h. Participants completed six satiety questionnaires. RESULTS: Plasma leptin, ghrelin and adiponectin did not differ between GTE and placebo at any time point; COMT genotype did not modify these results. Participants randomised to GTE with the high-activity form of COMT (GTE-high COMT) had higher insulin concentrations at time 0, 0.5 and 1.0 h post-meal compared to all COMT groups randomised to placebo. Insulin remained higher in the GTE-high COMT group at 1.5, 2.0 and 2.5 h compared to Placebo-low COMT (P < 0.02). GTE-high COMT had higher insulin concentrations at times 0, 0.5, 1.0, 1.5 and 2.0 h compared to the GTE-low COMT (P ≤ 0.04). Area under the curve measurements of satiety did not differ between GTE and placebo. CONCLUSIONS: GTE supplementation and COMT genotype did not alter acute post-prandial responses of leptin, ghrelin, adiponectin or satiety, although it may be involved in post-meal insulinaemic response of overweight and obese post-menopausal women.

Evidence that ghrelin may be associated with the food intake of gibel carp (Carassius auratus gibelio).

Ghrelin, a non-amidated peptide hormone, is a potent anorectic neuropeptide implicated in feeding regulation in mammals and non-mammalian vertebrates. However, the involvement of ghrelin in the feeding behavior of teleosts has not been well understood. To better understand the role of ghrelin in the regulation of appetite in fish, in this study, we cloned the cDNAs encoding ghrelin and investigated their mRNA distributions in gibel carp tissues. We also assessed the effects of different nutritional status on ghrelin mRNA abundance. Ghrelin mRNAs were ubiquitously expressed in ten tissues (intestine, liver, brain, mesonephron, head kidney, spleen, skin, heart, muscle, gill and pituitary gland), and relatively high expression levels were detected in the gut. Postprandial studies analysis revealed a significant postprandial decrease in ghrelin mRNA expression in the gut (1 and 3 h after the regular feeding time). In addition, ghrelin mRNA expression in the gut significantly increased at day 7 after fasting and declined sharply after refeeding, which suggested that ghrelin might be involved in the regulation of appetite in gibel carp. Overall, our result provides basis for further investigation into the regulation of feeding in gibel carp.

Postprandial kinetics of gene expression of proteins involved in the digestive process in rainbow trout (O. mykiss) and impact of diet composition.

The impact of increased incorporation of plant ingredients on diets for rainbow trout was evaluated in terms of gene expression of gastric (gastric lipase, pepsinogen) and intestinal (prolidase, maltase, phospholipase A2) digestive enzymes and nutrient transporters (peptide and glucose transporters), as well as of postprandial levels of plasma glucose, triglycerides and total free amino acids. For that purpose, trout alevins were fed from the start of exogenous feeding one of three different experimental diets: a diet rich in fish meal and fish oil (FM-FO), a plant-based diet (noFM-noFO) totally free from fish meal and fish oil, but containing plant ingredients and a Mixed diet (Mixed) intermediate between the FM-FO and noFM-noFO diets. After 16 months of rearing, all fish were left unfed for 72 h and then given a single meal to satiation. Blood, stomach and anterior intestine were sampled before the meal and at 2, 6 and 12 h after this meal. The postprandial kinetics of gene expression of gastric and intestinal digestive enzymes and nutrient transporters were then followed in trout fed the FM-FO diet. The postprandial profiles showed that the expression of almost all genes studied was stimulated by the presence of nutrients in the digestive tract of trout, but the timing (appearance of peaks) varied between genes. Based on these data, we have focused on the molecular response to dietary factors in the stomach and the intestine at 6 and 12 h after feeding, respectively. The reduction in FM and FO levels of dietary incorporation induced a significant decrease in the gene expression of gastric lipase, GLUT2 and PEPT1. The plasma glucose and triglycerides levels were also reduced in trout fed the noFM-noFO diet. Consequently, the present study suggests a decrease in digestive capacities in trout fed a diet rich in plant ingredients.

Postprandial molecular responses in the liver of the barramundi, Lates calcarifer.

The regulation of gene expression by nutrients is an important mechanism governing energy storage and growth in most animals, including fish. At present, very few genes that regulate intermediary metabolism have been identified in barramundi, nor is there any understanding of their nutritional regulation. In this study, a partial barramundi liver transcriptome was assembled from next-generation sequencing data and published barramundi EST sequences. A large number of putative metabolism genes were identified in barramundi, and the changes in the expression of 24 key metabolic regulators of nutritional pathways were investigated in barramundi liver over a time series immediately after a meal of a nutritionally optimised diet for this species. Plasma glucose and free amino acid levels showed a mild postprandial elevation which peaked 2 h after feeding, and had returned to basal levels within 4 or 8 h, respectively. Significant activation or repression of metabolic nuclear receptor regulator genes were observed, in combination with activation of glycolytic and lipogenic pathways, repression of the final step of gluconeogenesis and activation of the Akt-mTOR pathway. Strong correlations were identified between a number of different metabolic genes, and the coordinated co-regulation of these genes may underlie the ability of this fish to utilise dietary nutrients. Overall, these data clearly demonstrate a number of unique postprandial responses in barramundi compared with other fish species and provide a critical step in defining the response to different dietary nutrient sources.

Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.

Bile acids facilitate postprandial absorption of nutrients. Bile acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7α-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on bile acid synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, bile acid pool size, and serum bile acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of bile acid synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged bile acid pool with altered bile acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and bile acid synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes.

Molecular cloning, expression analysis, and potential food intake attenuation effect of peptide YY in grass carp (Ctenopharyngodon idellus).

The peptide YY (PYY) is a 36 amino acid peptide involved in the food intake control in vertebrates. We have cloned and characterized a PYY gene from grass carp Ctenopharyngodon idellus. The full-length cDNA encodes a precursor protein of grass carp PYY (gcPYY) that consists of a putative 28-amino acid signal peptide, a 36-amino acid mature peptide, an amidation-proteolytic site, and a 30-amino acid carboxy-terminal extension. The gcPYY gene is comprised of 4 exons interspaced by 3 introns as seen in PYYs from other species. Amino acid alignment and gene structure comparison indicate that the structure of PYY is well preserved throughout vertebrate phylogeny. The tissue distribution and postprandial changes in gcPYY mRNA expression were evaluated by real-time PCR, which showed that the gcPYY is expressed abundantly in the central nervous system, with significantly increased expression following a single meal. During embryogenesis, the presence of gcPYY mRNA was detected in early developing embryos, and high expression levels were observed when most larvae completed their switch from endogenous nourishment to exogenous feeding. Reduced food intake by juveniles during a single meal after giving perpheral injection of gcPYY1-36 suggests a potentially important role of PYY in the food intake attenuation in grass carp.

Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying.

Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor (DGAT1i) by oral gavage or genetic deletion of intestinal Dgat1 (intestine-Dgat1(-/-)) markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting chylomicron secretion in mice. Loss of DGAT1 activity did not affect the efficiency of retinol esterification, but it did reduce TG and retinoid accumulation in the small intestine. In contrast, inhibition of microsomal triglyceride transfer protein (MTP) reduced chylomicron secretion after oral fat/retinol loads, but with accumulation of dietary TG and retinoids in the small intestine. Lack of intestinal accumulation of TG and retinoids in DGAT1i-treated or intestine-Dgat1(-/-) mice resulted, in part, from delayed gastric emptying associated with increased plasma levels of glucagon-like peptide (GLP)-1. However, neither bypassing the stomach through duodenal oil injection nor inhibiting the receptor for GLP-1 normalized postprandial TG or retinyl esters excursions in the absence of DGAT1 activity. In summary, intestinal DGAT1 inhibition or deficiency acutely delayed gastric emptying and inhibited chylomicron secretion; however, the latter occurred when gastric emptying was normal or when lipid was administered directly into the small intestine. Long-term hepatic retinoid metabolism was not impacted by DGAT1 inhibition.

Whole transcriptome analysis of the fasting and fed Burmese python heart: insights into extreme physiological cardiac adaptation.

The infrequently feeding Burmese python (Python molurus) experiences significant and rapid postprandial cardiac hypertrophy followed by regression as digestion is completed. To begin to explore the molecular mechanisms of this response, we have sequenced and assembled the fasted and postfed Burmese python heart transcriptomes with Illumina technology using the chicken (Gallus gallus) genome as a reference. In addition, we have used RNA-seq analysis to identify differences in the expression of biological processes and signaling pathways between fasted, 1 day postfed (DPF), and 3 DPF hearts. Out of a combined transcriptome of ∼2,800 mRNAs, 464 genes were differentially expressed. Genes showing differential expression at 1 DPF compared with fasted were enriched for biological processes involved in metabolism and energetics, while genes showing differential expression at 3 DPF compared with fasted were enriched for processes involved in biogenesis, structural remodeling, and organization. Moreover, we present evidence for the activation of physiological and not pathological signaling pathways in this rapid, novel model of cardiac growth in pythons. Together, our data provide the first comprehensive gene expression profile for a reptile heart.

ABCA1 gene variants regulate postprandial lipid metabolism in healthy men.

OBJECTIVE: Genetic variants of ABCA1, an ATP-binding cassette (ABC) transporter, have been linked to altered atherosclerosis progression and fasting lipid concentration, mainly high-density lipoproteins and apolipoprotein A1; however, results from different studies have been inconsistent. METHODS AND RESULTS: To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. For i27943 and i48168 single nucleotide polymorphisms, fasting and postprandial values of apolipoprotein A1 were higher and postprandial lipemia was much lower in homozygotes for the major alleles, total triglycerides in plasma, and large triglyceride-rich lipoprotein triglycerides. These persons also showed a higher apolipoprotein A1/apolipoprotein B ratio. Major allele homozygotes for i48168 and i27943 showed additionally higher high-density lipoproteins and lower postprandial apolipoprotein B. CONCLUSION: Our work shows that major allele homozygotes for ABCA1 single nucleotide polymorphisms i27943 and i48168 have a lower postprandial response as compared to minor allele carriers. This finding may further characterize the role of ABCA1 in lipid metabolism.

Effect of the fat composition of a single high-fat meal on inflammatory markers in healthy young women.

The aim of the present study was to examine the effect of a single high-fat meal with different fat quality on circulating inflammatory markers and gene expression in peripheral blood mononuclear cells (PBMC) to elucidate the role of fat quality on postprandial inflammation. A postprandial study with fourteen healthy females consuming three test meals with different fat quality was performed. Test days were separated by 2 weeks. Fasting and postprandial blood samples at 3 and 6 h after intake were analysed. The test meal consisted of three cakes enriched with coconut fat (43 % energy as saturated fat and 1 % energy as α-linolenic acid (ALA)), linseed oil (14 % energy as ALA and 30 % energy as saturated fat) and cod liver oil (5 % energy as EPA and DHA and 5 % energy as ALA in addition to 31 % energy as saturated fat). In addition, ex vivo PBMC experiments were performed in eight healthy subjects investigating the effects of EPA and ALA on release and gene expression of inflammatory markers. The IL-8 mRNA level was significantly increased after intake of the cod liver oil cake at 6 h compared with fasting level, which was significantly different from the effect observed after the intake of linseed cake. In contrast, no effect was seen on circulating level of IL-8. In addition, ALA and EPA were shown to elicit different effects on the release and mRNA expression levels of inflammatory markers in PBMC cultured ex vivo, with EPA having the most prominent pro-inflammatory potential.

Postprandial effects on appetite-related neuropeptide expression in the brain of Atlantic salmon, Salmo salar.

Following feeding of a single meal to Atlantic salmon, the temporal changes in the brain mRNA expression of neuropeptide y (npy), cocaine-amphetamine regulated transcript (cart), peptide yy (pyy), two isoforms of agouti-related protein (agrp), two isoforms of cholecystokinin (cck), and four isoforms of proopiomelanocortin (pomc) were assessed by q-PCR. In the course of 24h post-feeding (hpf), several of the brain neuropeptides displayed changes in mRNA expression compared to an unfed control group, indicating that food intake and processing affect the regulation of expression of these genes in Atlantic salmon. Expression of cart, cck-l, pomc-a1 and pomc-b all increased within 3h of feeding, while most of the feed was still in the stomach, suggesting that these neuropeptides play central anorexigenic roles similar to those described in higher vertebrates, including determining meal intervals. On the other hand, the npy and agrp isoforms which have been described as playing orexigenic roles in mammals, showed an opposite response in salmon and both were elevated in the first 3h after feeding. The different isoforms of cck, agrp and pomc had different mRNA expression patterns, which indicate specific roles related to feeding regulation. The minimal effect of feeding and digestion on pyy expression in the brain indicates that PYY plays a minor role in the central control of short-term food intake in Atlantic salmon.

Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (ß [SE] -0.23 [0.03], P = 2.15 × 10-19). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: ß [SE] 0.17 [0.03], P = 5.76 × 10-10; XXLVLDL cholesterol ester: ß [SE] 0.17 [0.03], P = 9.74 × 10-10), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 × 10-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-ß, Matsuda insulin sensitivity index, and HbA1c in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes.

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study.

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10-8/132 = 4 × 10-10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10-7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10-3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.