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Purpose: The aim of this study was to investigate the long-term effects of almond consumption on peripheral vascular function, ambulant blood pressure profiles (ABP), and serum/plasma markers reflecting endothelial dysfunction and inflammation in participants with overweight/obesity and prediabetes., Methods: Thirty-four participants completed this single-blinded, randomized, cross-over trial with 5-month intervention and control periods, separated by a 2-month wash-out. During the intervention period, participants consumed 50 g of whole almonds daily. At the end of each intervention period, peripheral vascular function was assessed by measuring the carotid-to-femoral and carotid-to-radial pulse wave velocities (PWV c-f and PWV c-r , respectively) and retinal microvascular calibers. Serum/plasma concentrations of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNFα), serum amyloid A protein (SAA) and high-sensitivity C-reactive protein (hs-CRP) and 24-hour ABP were also analyzed., Results: Almond consumption did not significantly affect arterial stiffness (PWV c-f and PWV c-r ), while central retinal venular equivalent (CRVE) was minimally increased by 2 μm (P = 0.019). Central retinal arteriolar equivalent (CRAE), the arteriolar-to-venular ratio (AVR), and endothelial and inflammatory serum/plasma markers showed no significant changes after almond consumption. Almond consumption reduced systolic blood pressure (SBP; -3 mmHg 24-hour P = 0.035, -4 mmHg daytime P = 0.046, and - 4 mmHg during nighttime P = 0.029), SBP variability during 24-hour, daytime, and nighttime (P = 0.005, P = 0.019, and P = 0.003, respectively), and diastolic blood pressure variability during nighttime (P ≤ 0.001)., Conclusion: Almond consumption did not affect arterial stiffness, retinal microvasculature calibers, or serum and plasma markers for endothelial dysfunction and inflammation in participants with prediabetics, while BP and BP variability were improved., Clinical Trial Registration: This clinical trial was registered in February 2018 as NCT03419702., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

A well-functioning immune system requires balanced immune responses. In vitro studies have shown that plant stanols contribute to restoring the T-helper (Th)1/Th2 ratio when it is imbalanced. However, effects of plant stanols on healthy immune responses are unknown. Therefore, we studied effects of recommended (2·5 g/d) or high (9·0 g/d) plant stanol intakes on the Th1/Th2 cytokine balance in immunologically healthy subjects. In two RCTs, peripheral blood mononuclear cells (PBMCs) were isolated, cultured, and stimulated with 5 µg/ml Phytohemagglutinin-M to study ex vivo cytokine production. In the first study, twenty participants consumed margarines (2·5 g/d plant stanols) or control for three weeks. In the second study, nineteen participants consumed margarines and yogurts (9·0 g/d plant stanols) or control for four weeks. T-cell cytokine concentrations were measured in culture medium and in study 2 a standardized Th1/Th2 index was calculated. Serum lipids and non-cholesterol sterols were also measured. Compliance was confirmed by significant increases in serum total cholesterol (TC)-standardized sitostanol and campestanol levels in both studies. Changes in ex vivo cytokine production and Th1/Th2 index did not differ between intervention and control groups. In the first study, no statistically significant changes were observed in lipid and lipoprotein concentrations. In the second study, LDL cholesterol significantly decreased compared to control (-0·77 (-1·11, -0·42) mmol/l; P < 0·001). Recommended (2·5 g/d) or high (9·0 g/d) intakes of plant stanols did not alter PBMC ex vivo cytokine production in immunologically healthy subjects. This suggests that plant stanols might only affect immune function when Th1/Th2 immune responses are imbalanced.

The incidence of cognitive decline is rising, leading to increased attention on the preventive role of healthy foods on brain function. Previous reviews including primarily observational studies suggested that dietary proteins may improve cognitive performance, but evidence from individual randomised controlled trials (RCT) is less consistent. Therefore, this systematic review examined the long-term effects of dietary proteins from RCT, considering both their amount and type, on cognitive performance (psychomotor speed and attention, executive function, memory and global cognition). Alterations in cerebral blood flow (CBF) - a validated brain vascular function marker - were also considered. A total of 4747 studies were identified through a systematic search, resulting in twenty-three included papers reporting effects on cognitive performance ( n = 23) and CBF ( n = 3). Improvements were observed in three out of the nine studies that evaluated psychomotor speed which compared a dietary protein intervention with a non-protein or lower-protein control. Of the six beneficial observations on working memory ( n = 12), declarative memory ( n = 10) and visuospatial memory ( n = 10), five were nut interventions from three different trials. Limited studies focusing on global cognition suggested that specific target populations, namely subacute stroke or dementia, may benefit more than healthy individuals from increased dietary protein intake. From the three studies involving CBF, improvements in regional blood flow were associated with most cognitive performance outcomes. The comparative effects of different protein types warrant further investigation. Overall, this review encourages additional research into protein-rich foods or supplements which could potentially prevent or mitigate cognitive decline.

Purpose: Short-term intake of the egg-protein hydrolysate Newtricious (NWT)-03 improved executive function, but underlying mechanisms and long-term effects, including other cognitive domains, are unknown., Methods: A 36-week randomized controlled trial involving 44 overweight/obese individuals experiencing elevated Subjective Cognitive Failures (SCF; aged 60-75 years) assessed the impact of daily consumption of 5.7 g of NWT-03 or placebo powders on cognitive performance (psychomotor speed, executive function, memory) and Cerebral Blood Flow (CBF), a marker of brain vascular function. Cognitive performance was evaluated using a neurophysiological test battery (CANTAB) and CBF was measured using magnetic resonance imaging perfusion method Arterial Spin Labeling (ASL). Serum samples were collected to determine brain-derived neurotrophic factor (BDNF) concentrations., Results: Anthropometrics, and energy and nutrient intakes remained stable throughout the trial. NWT-03 was well tolerated, and compliance was excellent (median: 99%; range: 87-103%). No overall intervention effects were observed on cognitive performance or CBF, but post-hoc analyses revealed significant improvements on executive function in women, but not men. Specifically, a reduction of 74 ms in reaction latency on the multitasking task (95% CI: -134 to -15; p = 0.02), a reduction of 9 between errors (95%CI: -14 to -3; p < 0.001), and a reduction of 9 total errors (95%CI: -15 to -3; p < 0.001) on the spatial working memory task were found in women. No intervention effects were observed on serum BDNF concentrations (p = 0.31)., Conclusion: Long-term consumption of NWT-03 improved multitasking abilities and working memory in women with elevated SCF. Brain vascular function remained unaffected. Sex differences in executive function require additional clarification., (© 2024. The Author(s).)

Background: People with overweight/obesity generally have impaired immune responses, resulting among others in increased risk of severe complaints and hospitalization after infections with severe acute respiratory syndrome coronavirus 2 (COVID-19), as well as decreased antibody production after vaccinations. Plant stanol ester previously increased the combined IgM/IgG antibody titers toward a hepatitis A vaccination in patients with allergic asthma, but the underlying mechanism is unknown., Objectives: We evaluated whether plant stanol ester consumption improved the immune response in subjects with overweight/obesity after a COVID-19 vaccination., Methods: A double-blind, randomized, placebo-controlled trial was performed. Thirty-two subjects with overweight/obesity consumed products with added plant stanols (4 g/d; provided as plant stanol ester) or control ≥2 wk before receiving their COVID-19 vaccination until 4 wk after vaccination. Antibody titers were analyzed weekly and statistically analyzed using mixed models. Serum metabolic markers and cytokine profiles were also analyzed., Results: IgM concentrations against the COVID-19 Spike protein were increased in the plant stanol ester group compared with the control group, with the largest difference observed 2 wk after vaccination [31.2 (0.43, 62.1) BAU/mL, or +139%; Group × Time: P = 0.031]. Subjects that produced very low IgM antibodies produced, as expected, hardly any IgG antibodies. In those with IgG seroconversion, IgG Spike concentrations were also increased in the plant stanol ester group compared with the control group [71.3 (2.51, 140.1) BAU/mL; Group P = 0.043]. Stimulated cytokine concentrations decreased in the plant stanol ester group compared with the control group in all 3 cytokine domains (that is, proinflammatory, T helper [Th1]/Th17, and Th2/regulatory T cells). Between-group differences in serum LDL cholesterol or other metabolic markers were not observed., Conclusions: Consuming plant stanols (4 g/d) affects immune responses to COVID-19 vaccinations, translating into increased serum anti-COVID-19 IgM concentrations in subjects with overweight/obesity. Only in IgG seroconverted subjects, serum anti-COVID-19 IgG concentrations also increase. These effects are independent of reductions in LDL cholesterol. These results suggest that this high-risk group for COVID-19 complications could benefit from plant stanol consumption. This trial was registered at clinicaltrials.gov as NCT04844346., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Improving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases., Objectives: This study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity., Methods: In a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m 2 ) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed., Results: Body weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: -4.5 ± 4.7 mL/100 g/min; P < 0.001; -4.6 ± 4.8 mL/100 g/min; P < 0.001; and -4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (-4.3 ± 5.6 mL/100 g/min; and -3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (-5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (-0.7%-point; 95% CI: -1.3%-point to -0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (-0.24 mmol/L; 95% CI: -0.44 to -0.04 mmol/L; P = 0.019), and systolic blood pressure (-5 mm Hg; 95% CI: -8 to -1 mm Hg; P = 0.006) were lower after the mixed nut intervention., Conclusions: Longer-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected. This trial was registered at clinicaltrials.gov as NCT04210869., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The interest in intermittent energy restriction (IER) diets as a weight-loss approach is increasing. Different IER protocols exist, including time-restricted eating (TRE), alternate-day fasting (ADF), and the 5:2 diet. This meta-analysis compared the effects of these IER diets with continuous energy restriction (CER) on anthropometrics and cardiometabolic risk markers in healthy adults. Twenty-eight trials were identified that studied TRE (k = 7), ADF (k = 10), or the 5:2 diet (k = 11) for 2-52 wk. Energy intakes between intervention groups within a study were comparable (17 trials), lower in IER (5 trials), or not reported (6 trials). Weighted mean differences (WMDs) were calculated using fixed- or random-effects models. Changes in body weight [WMD: -0.42 kg; 95% confidence interval (CI): -0.96 to 0.13; P = 0.132] and fat mass (FM) (WMD: -0.31 kg; 95% CI: -0.98 to 0.36; P = 0.362) were comparable when results of the 3 IER diets were combined and compared with those of CER. All IER diets combined reduced fat-free mass (WMD: -0.20 kg; 95% CI: -0.39 to -0.01; P = 0.044) and waist circumference (WMD: -0.91 cm; 95% CI: -1.76 to -0.06; P = 0.036) more than CER. Effects on body mass index [BMI (kg/m 2 )], glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), serum lipid and lipoprotein concentrations, and blood pressure did not differ. Further, TRE reduced body weight, FM, and fat-free mass more than CER, whereas ADF improved HOMA-IR more. BMI was reduced less in the 5:2 diet compared with CER. In conclusion, the 3 IER diets combined did not lead to superior improvements in anthropometrics and cardiometabolic risk markers compared with CER diets. Slightly greater reductions were, however, observed in fat-free mass and waist circumference. To what extent differences in energy intakes between groups within studies may have influenced these outcomes should be addressed in future studies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The metabolic syndrome is associated with cardiovascular diseases and cognitive decline. The egg protein hydrolysate NWT-03 has shown to improve cardiovascular risk factors in humans. This study investigated whether NWT-03 also has an effect on cognitive function. Methods: Men and women with the metabolic syndrome ( n  = 76) with a mean age of 60 ± 10 years participated in this randomized, double-blind, placebo-controlled, cross-over trial with an intervention (5 g/day NWT-03) and control period (5 g/day maltodextrin) of 4 weeks separated by a wash-out period of 2-8 weeks. Cognitive function was assessed with the anti-cue reaction time test (impulse control) and psychomotor vigilance test (sustained attention) at day 0, 2, and 27 of both periods. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured at the start and end of both periods. Results: NWT-03 consumption significantly improved the change (day 27 - day 0) in response times of the anti-cue reaction time test compared with the control period ( P  < 0.001), but not of the psychomotor vigilance test ( P  = 0.487). Serum BDNF concentrations of all subjects did not significantly change ( P  = 0.241). Conclusion: NWT-03 has the ability to improve cognitive function within the executive function domain. The underlying mechanism warrants further research and could either be indirect via inhibition of dipeptidyl peptidase 4 (DPP4) or direct via passage of small peptides over the blood-brain barrier inducing local effects. Trial registration: ClinicalTrials.gov identifier: NCT02561663.

Background: Short-term intake of egg-derived protein hydrolysates, such as NWT-03, suggest improvements in arterial stiffness and metabolic profiles, but longer-term trials are lacking. This study therefore examined the longer-term effects of NWT-03 on arterial stiffness and cardiometabolic markers in men and women with metabolic syndrome., Methods: Seventy-six adults with metabolic syndrome (age 61 ± 10 years; BMI 31.7 ± 4.0 kg/m 2 ) participated in a randomized, controlled, double-blind, cross-over trial with a 27-day intervention (5 g/day NWT-03) or placebo period, separated by two-to-eight weeks of washout. At the start and end of both periods, measurements were performed in the fasting state and 2 h following acute NWT-03 intake. Arterial stiffness was assessed by carotid-to-radial (PWV c-r ), carotid-to-femoral pulse wave velocity (PWV c-f ), and central augmentation index (CAIxHR75). Moreover, cardiometabolic markers were assessed., Results: Compared with control, longer-term NWT-03 supplementation did not affect fasting PWV c-r (0.1 m/s; -0.2 to 0.3; P = 0.715) or PWV c-f (-0.2 m/s; -0.5 to 0.1; P = 0.216). Fasting pulse pressure (PP) was however reduced by 2 mmHg (95% CI: -4 to 0; P = 0.043), but other fasting cardiometabolic markers were not affected. No effects were observed following acute NWT-03 intake at baseline. However, acute intake of NWT-03 after the intervention significantly lowered CAIxHR75 (-1.3%-point; -2.6 to -0.1; P = 0.037) and diastolic BP (-2 mmHg; -3 to 0; P = 0.036), but other cardiometabolic markers did not change., Conclusion: Longer-term NWT-03 supplementation did not affect arterial stiffness, but modestly improved fasting PP in adults with metabolic syndrome. Acute intake of NWT-03 after the intervention also improved CAIxHR75 and diastolic BP., Trial Registration: The study was registered at ClinicalTrials.gov as NCT02561663., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Findings concerning the effects of almond consumption on glucose metabolism are inconsistent which might relate to body weight gain. The effects of long-term almond consumption on glucose metabolism are investigated in a free-living setting without detailed dietary instructions in males and females with overweight/obesity and prediabetes., Methods: Forty-three participants volunteered in this randomized, cross-over trial with a 5-months control and intervention period and a 2-months wash-out. In the intervention period participants daily consumed 50 g whole almonds. At the end of both periods insulin sensitivity was assessed by a hyperinsulinemic euglycemic clamp, and postprandial glucose responses, and 48 h continuous glucose concentrations were measured., Results: Almond consumption significantly decreased insulin sensitivity (P = 0.002), and increased postprandial glucose concentrations (P = 0.019), as well as fasting insulin concentrations (P = 0.003) as compared to the control period. The AUCs for 24 h glucose concentrations were not significantly different between control and intervention (P = 0.066). Almond consumption also significantly increased BMI (P = 0.002), and waist circumference (P = 0.013), supported by the concurrent increased energy intake (P = 0.031). The effects on glucose metabolism could only partly be explained by the observed weight gain as the almond effect remained after correcting for BMI changes., Conclusions: In participants with prediabetes, long-term almond consumption showed adverse effects on insulin sensitivity and glucose metabolism. As almonds seemed not to have fully replaced other food items, it might be necessary to provide more supporting guidelines on how to incorporate energy-dense nuts into healthy diets to prevent type 2 diabetes development., Clinical Trial Registration: This clinical trial was registered in February 2018 as NCT03419702., (© 2023. The Author(s).)

Background: Nut consumption may reduce age-related cognitive decline, but underlying mechanisms are unclear., Objective: To investigate in older adults longer-term effects of mixed nut consumption on brain vascular function, which may underlie improvements in cognitive performance., Methods: Twenty-eight healthy individuals (age [mean ± SD]: 65 ± 3 years; BMI: 27.9 ± 2.3 kg/m 2 ) were included in a randomized, single-blinded, cross-over trial with a 16-week intervention (60 g/d mixed nuts: walnuts, pistachio, cashew, and hazelnuts) and control period (no nuts), separated by 8 weeks of washout. Participants followed the Dutch food-based dietary guidelines. At the end of each period, cerebral blood flow (CBF), a marker of brain vascular function, was quantified using arterial spin labeling magnetic resonance imaging. Effects on endothelial function, arterial stiffness, and the retinal microvasculature were also assessed. Cognitive performance was measured using the Cambridge Neuropsychological Test Automated Battery., Results: Body weight remained stable during the study. As compared to the control period, the mixed nut intervention resulted in a higher regional CBF in the right frontal and parietal lobes (treatment effect: 5.0 ± 6.5 mL/100 g/min; P < 0.001), left frontal lobe (5.4 ± 7.1 mL/100 g/min; P < 0.001), and bilateral prefrontal cortex (5.6 ± 6.6 mL/100 g/min; P < 0.001). Carotid artery reactivity (0.7 PP; 95%CI: 0.2 to 1.2; P = 0.007), brachial flow-mediated vasodilation (1.6 PP; 95%CI: 1.0 to 2.2; P < 0.001) and retinal arteriolar calibers were higher (2 μm; 95%CI: 0 to 3; P = 0.037), and carotid-to-femoral pulse wave velocity lower (-0.6 m/s; 95%CI: -1.1 to -0.1; P = 0.032). Further, visuospatial memory (-4 errors [16%]; 95%CI: -8 to 0; P = 0.045) and verbal memory (+1 correct [16%]; 0 to 2; P = 0.035) improved, but executive function and psychomotor speed did not change., Conclusions: Longer-term mixed nut consumption as part of a healthy diet beneficially affected brain vascular function, which may relate to the observed beneficial effects on memory in older adults. Moreover, different characteristics of the peripheral vascular tree also improved., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Single nucleotide polymorphisms (SNPs) in circadian clock relevant genes are associated with several metabolic health variables, but little is known about their associations with human cholesterol metabolism. Therefore, this study examined associations between SNPs in ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER2, and PER3 with the intestinal cholesterol absorption markers campesterol and sitosterol, the endogenous cholesterol synthesis marker lathosterol, and total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations in 456 healthy individuals from Western European descent. One SNP in ARNTL2 (rs1037924) showed a significant association with lathosterol. Several SNPs in ARNTL (rs4146388, rs58901760, rs6486121), ARNTL2 (rs73075788), CLOCK (rs13113518, rs35115774, rs6832769), and CRY1 (rs2078074) were significantly associated with intestinal cholesterol absorption. Genetic variants in CRY2, PER2, and PER3 were not significantly associated with intestinal cholesterol absorption or endogenous cholesterol synthesis. None of the SNPs were associated with TC or LDL-C, except for one SNP in PER2 (rs11894491) with serum LDL-C concentrations. The findings suggest that various SNPs in ARNTL, ARNTL2, CLOCK and CRY1 play a role in intestinal cholesterol absorption and endogenous cholesterol synthesis, which was not reflected in TC and LDL-C concentrations. The significant associations between SNPs and intestinal cholesterol absorption and endogenous cholesterol synthesis should be validated in other cohorts., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current guidelines aim to limit the dietary glycemic index (GI) and intake of saturated fatty acids (SFA). Several studies have shown favorable effects of low-GI or low-SFA diets on intrahepatic lipid content (IHL), but these studies were performed under overfeeding conditions or extreme differences in GI or SFA to maximize the contrast between diets. By combining changes in GI and SFA, we can mimic how people can improve their diet in a realistic setting., Objectives: We investigated the effect on liver fat content and substrate metabolism of both reducing GI and replacing SFA with polyunsaturated fat in practically realistic amounts under isocaloric conditions., Design and Methods: In a randomized crossover study, thirteen overweight participants consumed two diets, one high in GI and SFA (high GI/SFA) and one low in GI and SFA (low GI/SFA) with identical macronutrient composition, for two weeks each. Diets were equal in caloric content, consisted of habitual food items, and had a macronutrient composition that can be easily achieved in daily life. At the end of each intervention, IHL content/composition and liver glycogen were measured by magnetic resonance spectroscopy. Additionally, fasted and postprandial hepatic de novo lipogenesis and glycemic and metabolic responses were investigated., Results: IHL was significantly lower (-28%) after the two-week low-GI/SFA diet (2.4 ± 0.5% 95% CI [1.4, 3.4]) than after the two-week high-GI/SFA diet (3.3 ± 0.6% 95% CI [1.9, 4.7], p < 0.05). Although hepatic glycogen content, hepatic de novo lipogenesis, hepatic lipid composition, and substrate oxidation during the night were similar between the two diets, the glycemic response to the low-GI/SFA diet was reduced ( p < 0.05)., Conclusions: Changes in macronutrient quality can already have drastic effects on liver fat content and postprandial glycemia after two weeks and even when energy content and the percentage of total fat and carbohydrate remains unchanged.

Inflammation is associated with changes in plasma lipids, lipoproteins, and cholesterol efflux capacity (CEC). It is unknown if the changes in lipids and lipoproteins during inflammation are related to changes in cholesterol absorption, synthesis, and bile acid synthesis. We, therefore, examined the effects of acute lipopolysaccharide (LPS)-induced transient systemic inflammation on lipids, lipoproteins, CEC, and markers of cholesterol metabolism. We also evaluated whether markers for cholesterol metabolism at baseline predict the intensity of the inflammatory response. Eight healthy young subjects received LPS infusion, and blood was sampled for the following 24 h. In addition to lipids, lipoproteins, and CEC, we also measured markers for cholesterol absorption and synthesis, bile acid synthesis, and inflammation. Compared with baseline, plasma total cholesterol, low-density lipoprotein cholesterol, and CEC decreased, while triglycerides increased in the 24 h following LPS infusion. TC-standardized levels of cholesterol synthesis markers (lathosterol, lanosterol, and desmosterol) and a bile acid synthesis marker (7α-OH-cholesterol) also decreased, with no changes in cholesterol absorption markers (campesterol, sitosterol, and cholestanol). Baseline TC-standardized levels of desmosterol and 7α-OH-cholesterol were positively correlated with concentrations of various inflammatory markers. Changes in TC-standardized desmosterol and 7α-OH-cholesterol were negatively correlated with concentrations of inflammatory markers. LPS infusion reduced endogenous cholesterol synthesis and bile acid synthesis in healthy young men.

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatic free cholesterol accumulation. In addition, microRNAs (miRNAs) might be involved in NAFLD development. Therefore, we systematically reviewed the literature to examine the link between miRNAs and cholesterol metabolism in NAFLD. Nineteen studies were retrieved by a systematic search in September 2022. From these papers, we evaluated associations between 13 miRNAs with NAFLD and cholesterol metabolism. Additionally, their diagnostic potential was examined. Four miRNAs (miR122, 34a, 132 and 21) were associated with cholesterol metabolism and markers for NAFLD. MiR122 was upregulated in serum of NAFLD patients, increased with disease severity and correlated with HDL-C, TAG, VLDL-C, AST, ALT, ALP, lobular inflammation, hepatocellular ballooning and NAFLD score. Serum and hepatic levels also correlated. Serum and hepatic miR34a levels were increased in NAFLD, and correlated with VLDL-C and TAG. Serum miR379 was also higher in NAFLD, especially in early stages, while miR21 gave ambiguous results. The diagnostic properties of these miRNAs were comparable to those of existing biomarkers. However, serum miR122 levels appeared to be elevated before increases in ALT and AST were evident. In conclusion, miR122, miR34a, miR21 and miR132 may play a role in the development of NAFLD via effects on cholesterol metabolism. Furthermore, it needs to be explored if miRNAs 122, 34a and 379 could be used as part of a panel in addition to established biomarkers in early detection of NAFLD.

The aim of this systematic review was to examine the effects of physical exercise training on cerebral blood flow (CBF), which is a physiological marker of cerebrovascular function. Relationships between training-induced effects on CBF with changes in cognitive performance were also discussed. A systematic search was performed up to July 2022. Forty-five intervention studies with experimental, quasi-experimental, or pre-post designs were included. Sixteen studies (median duration: 14 weeks) investigated effects of physical exercise training on CBF markers using magnetic resonance imaging, 20 studies (median duration: 14 weeks) used transcranial Doppler ultrasound, and eight studies (median duration: 8 weeks) used near-infrared spectroscopy. Studies using magnetic resonance imaging observed consistent increases in CBF in the anterior cingulate cortex and hippocampus, but not in whole-brain CBF. Effects on resting CBF-measured with transcranial Doppler ultrasound and near-infrared spectroscopy-were variable, while middle cerebral artery blood flow velocity increased in some studies following exercise or hypercapnic stimuli. Interestingly, concomitant changes in physical fitness and regional CBF were observed, while a relation between training-induced effects on CBF and cognitive performance was evident. In conclusion, exercise training improved cerebrovascular function because regional CBF was changed. Studies are however still needed to establish whether exercise-induced improvements in CBF are sustained over longer periods of time and underlie the observed beneficial effects on cognitive performance.

Most trials on the effects of inorganic nitrate intake have focused on only one specific aspect of the endothelial cell response to a stimulus, thereby possibly missing other important effects. The aim of the present randomized, double-blinded, placebo-controlled cross-over study was therefore to investigate in eighteen healthy abdominally obese men (18-60 years, waist circumference ≥ 102 cm) acute effects of potassium nitrate on brachial and femoral flow-mediated vasodilation (FMD), and on carotid artery reactivity (CAR) to a cold pressure test. Participants received in random order a drink providing 10 mmol potassium nitrate (i.e., 625 mg of nitrate) or an iso-molar placebo drink with potassium chloride. Fasted and 4 h post-drink FMD and blood pressure measurements were performed. CAR responses were assessed at 4 h. Circulating nitrate plus nitrite concentration increased following nitrate intake ( p = 0.003). Compared with placebo, potassium nitrate did not affect brachial (mean [95% confidence interval]: -0.2% [-2.5, 2.1], p = 0.86) and femoral FMD responses (-0.6% [-3.0; 1.7], p = 0.54). CAR responses were also not different (-0.8% [-2.5, 0.9], p = 0.32). Finally, changes in blood pressure and heart rate did not differ. No adverse events were observed. In conclusion, this trial did not provide evidence for effects of a single dose of inorganic nitrate on 4 h vascular endothelial function in abdominally obese men.

Whether older adults need more protein than younger adults is debated. The population reference intake for adults set by the European Food Safety Authority is 0.83 g/kg body weight (BW)/d based primarily on nitrogen balance studies, but the underlying data on health outcomes are outdated. An expert committee of the Health Council of the Netherlands conducted a systematic review (SR) of randomized controlled trials (RCTs) examining the effect of increased protein intake on health outcomes in older adults from the general population with an average habitual protein intake ≥0.8 g/(kg BW · d). Exposures were the following: 1) extra protein compared with no protein and 2) extra protein and physical exercise compared with physical exercise. Outcomes included lean body mass, muscle strength, physical performance, bone health, blood pressure, serum glucose and insulin, serum lipids, kidney function, and cognition. Data of >1300 subjects from 18 RCTs were used. Risk of bias was judged as high (n = 9) or "some concerns" (n = 9). In 7 of 18 RCTs, increased protein intake beneficially affected ≥1 of the tested outcome measures of lean body mass. For muscle strength, this applied to 3 of 8 RCTs in the context of physical exercise and in 1 of 7 RCTs without physical exercise. For the other outcomes, <30% (0-29%) of RCTs showed a statistically significant effect. The committee concluded that increased protein intake has a possible beneficial effect on lean body mass and, when combined with physical exercise, muscle strength; likely no effect on muscle strength when not combined with physical exercise, or on physical performance and bone health; an ambiguous effect on serum lipids; and that too few RCTs were available to allow for conclusions on the other outcomes. This SR provides insufficiently convincing data that increasing protein in older adults with a protein intake ≥0.8 g/(kg BW · d) elicits health benefits., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

It is well-known that aerobic exercise training beneficially affects endothelial function as measured by brachial artery flow-mediated vasodilation (FMD). This trial with older sedentary overweight and obese men, therefore, examined the effects of aerobic training on other non-invasive markers of the vasculature, which have been studied in less detail. Seventeen men (67 ± 2 years, BMI: 30.3 ± 2.8 kg/m 2 ) participated in this controlled cross-over study. Study participants followed in random order a fully supervised, progressive, aerobic exercise training (three 50-min sessions each week at 70% maximal power) and a no-exercise control period for 8 weeks, separated by a 12-week wash-out period. At the end of each period, endothelial function was assessed by the carotid artery reactivity (CAR) response to a cold pressor test and FMD, and local carotid and regional aortic stiffness by the carotid-to-femoral pulse wave velocity (PWV c-f ). The retinal microvasculature, the serum lipid profile, 24-h ambulatory blood pressure, and 96-h continuous glucose concentrations were also determined. Aerobic training increased CAR from 1.78% to 4.01% (Δ2.23 percentage point [pp]; 95% CI: 0.58, 3.89 pp; p = 0.012) and FMD from 3.88% to 6.87% (Δ2.99 pp; 95% CI: 0.58, 5.41 pp; p = 0.019). The stiffness index β 0 increased by 1.1 (95% CI: 0.3, 1.9; p = 0.012), while PWV c-f did not change. Retinal arteriolar width increased by 4 μm (95% CI: 0, 7 μm; p = 0.041). Office blood pressure decreased, but ambulatory blood pressure, and serum lipid and continuous glucose concentrations did not change. Aerobic exercise training improved endothelial function and retinal arteriolar width in older sedentary overweight and obese men, which may reduce cardiovascular risk., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Little is known of the impact of individual SFAs and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review assessed the impact of such dietary substitutions on a range of fasting CMD risk markers, including lipid profile, markers of glycemic control and inflammation, and metabolic hormone concentrations. Eligible randomized controlled trials (RCTs) investigated the effect of isoenergetic replacements of individual dietary SFAs for ≥14 d on ≥1 CMD risk markers in humans. Searches of the PubMed, Embase, Scopus, and Cochrane CENTRAL databases on 14 February, 2021 identified 44 RCTs conducted in participants with a mean ± SD age of 39.9 ± 15.2 y. Studies' risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 for RCTs. Random-effect meta-analyses assessed the effect of ≥3 similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in LDL-cholesterol concentrations after the replacement of palmitic acid (16:0) with UFAs (-0.36 mmol/L; 95% CI: -0.50, -0.21 mmol/L; I2 = 96.0%, n = 18 RCTs) or oleic acid (18:1n-9) (-0.16 mmol/L; 95% CI: -0.28, -0.03 mmol/L; I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apoB concentrations. No effects on other CMD risk markers, including HDL-cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid (18:0) with UFAs on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFAs on lipid biomarkers is aligned with current public health recommendations. However, owing to the high heterogeneity and limited studies, relations between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs. This systematic review was registered at www.crd.york.ac.uk/prospero/ as CRD42020084241., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction., Methods: The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention., Results: The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule., Conclusions: Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Objectives: Brain-derived neurotrophic factor (BDNF) plays an essential role in brain and metabolic health. The fact that higher concentrations are associated with improved cognitive performance has resulted in numerous intervention trials that aim at elevating BDNF levels. This systematic review provides an overview of the relation between various nutritional factors and BDNF concentrations in controlled human intervention studies. Methods: A systematic search in May 2020 identified 48 articles that examined the effects of dietary patterns or foods ( n = 3), diets based on energy intake ( n = 7), vitamins and minerals ( n = 7), polyphenols ( n = 11), long-chain omega-3 polyunsaturated fatty acids ( n = 5), probiotics ( n = 8), and miscellaneous food supplements ( n = 7). Results: In particular, studies with dietary patterns or foods showed increased peripheral BDNF concentrations. There are also strong indications that polyphenols tend to have a positive effect on BDNF concentrations. Four of the 11 included studies with a polyphenol intervention showed a significant increase in BDNF concentrations, one study showed an increase but this was not statistically analyzed, and two studies showed a trend to an increase. Discussion: The two polyphenol classes, phenolic acids, and other phenolic compounds were responsible for the significant effects. No clear effect was found for the other dietary factors, which might also be related to whether serum or plasma was used for BDNF analysis. More work is needed to understand the relation between peripheral and central BDNF concentrations.

A higher concentration of apolipoprotein A-I (ApoA-I) is associated with increased high density lipoprotein functionality and reverse cholesterol transport (RCT). A promising strategy to prevent cardiovascular diseases is therefore to improve RCT by increasing de novo ApoA-I production. Since experimental animal models have suggested effects of amino acids on hepatic lipoprotein metabolism, we here examined the effects of different amino acids on hepatic ApoA-I production. Human hepatocytes (HepG2) were exposed to six individual amino acids for 48 h. ApoA-I transcription and secreted pro-ApoA-I protein concentrations were analyzed using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assays (ELISA), respectively. Additionally, CPT1 and KEAP1 mRNA expression, peroxisome proliferator-activated receptor alpha (PPARα) transactivation, and mechanistic target of rapamycin complex 1 (mTORC1) phosphorylation were determined. Leucine, glutamic acid, and tryptophan increased ApoA-I and CPT1 mRNA expression. Tryptophan also strongly increased PPARα transactivation. Glutamine, proline, and histidine increased pro-ApoA-I protein concentrations but mTORC1 phosphorylation remained unchanged regardless of the amino acid provided. In conclusion, individual amino acids have different effects on ApoA-I mRNA expression and pro-ApoA-I production which can partially be explained by specific effects on PPARα transactivation, while mTORC1 phosphorylation remained unaffected.

Background: Soy foods may contribute to the beneficial health effects of healthy plant-based diets on the risk to develop cardiovascular disease (CVD). However, their effects on vascular function have hardly been studied., Objective: To investigate longer-term effects of soy nut consumption on vascular function and cardiometabolic risk markers in healthy older men and women., Design: Twenty-three healthy participants (age: 60-70 years; BMI: 20-30 kg/m 2 ) participated in a randomized, controlled, single-blinded cross-over trial with an intervention (67 g/day of soy nuts providing 25.5 g protein and 174 mg isoflavones) and control period (no nuts) of 16 weeks, separated by eight weeks wash-out. Adults followed the Dutch food-based dietary guidelines., Results: No serious adverse events were reported and the soy nut regime was well tolerated. Body weights remained stable during the whole study. A higher protein (3.1 energy percent [En%]) and a lower carbohydrate intake (2.0 En%) was observed during the intervention period. Total fat intake was comparable, but that of saturated (-1.3 En%), cis-monounsaturated (-1.5 En%) and cis-polyunsaturated fatty acids (+1.9 En%) differed. Serum isoflavone concentrations were higher after the intervention as compared with the control period (daidzein: 127.8 ng/mL; 95% CI: 74.3-181.3 ng/mL; p < 0.001 and genistein: 454.2 ng/mL; 95% CI: 266.6-641.8 ng/mL; p < 0.001). Brachial artery flow-mediated vasodilation was 1.48 percent points (pp; 95% CI: 0.08-2.89 pp; p = 0.040) higher following soy nut intake. The carotid artery reactivity response and arterial stiffness did not differ. Serum LDL-cholesterol was lower (0.17 mmol/L; 95% CI: 0.02-0.32 mmol/L; p = 0.027), while HDL-cholesterol and triacylglycerol concentrations were comparable. Mean arterial pressure (MAP) was lower (3 mmHg; 95% CI: 0-6 mmHg; p = 0.035)., Conclusions: Longer-term soy nut intake as part of a healthy diet improved endothelial function, LDL-cholesterol concentrations and MAP levels, suggesting mechanisms by which an increased soy food intake beneficially affects CVD risk in older adults. Registered under ClinicalTrials.gov Identifier no. NCT03627637., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.

Intestinal cholesterol absorption varies widely between individuals, which may translate into differences in responsiveness to cholesterol-lowering drugs or diets. Therefore, understanding the importance of genetic variation on cholesterol absorption rates and the complex intestinal cholesterol network is important. Based on a systematic review, genetic variants in seven genes (ABCG5, ABCG8, ABO, APOE, MTTP, NPC1L1, and LDLR) were identified that were associated with intestinal cholesterol absorption. No clear associations were found for variants in APOA4, APOB, CETP, CYP7A1, HMGCR, SCARB1, SLCO1B1, and SREBF1. The seven genes were used to construct an intestinal cholesterol absorption network. Finally, a network with fifteen additional genes (APOA1, APOA4, APOB, APOC2, APOC3, CETP, HSPG2, LCAT, LDLRAP1, LIPC, LRP1, OLR1, P4HB, SAR1B, and SDC1) was generated. The constructed network shows that cholesterol absorption is complex. Further studies are needed to validate and improve this network, which may ultimately lead to a better understanding of the wide inter-individual variability in intestinal cholesterol absorption and the development of personalized interventions., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aimed to explore associations between non-cholesterol sterol concentrations in breast milk and allergic outcomes in children aged two. Data from the KOALA Birth Cohort Study, the Netherlands, were used. Non-cholesterol sterols were analyzed by gas-liquid chromatography-mass spectrometry in breast milk sampled one-month postpartum ( N = 311). Sterols were selected for each allergic outcome, i.e., eczema, wheeze, and allergic sensitization, prior to analyses. Associations between the selected sterols with allergic outcomes were analyzed using multiple logistic regression to calculate odds ratios (ORs). The odds of eczema in the first two years of life were lower with higher concentrations of cholestanol (OR (95%CI): 0.98 (0.95; 1.00), p = 0.04), lanosterol (0.97 (0.95; 1.00), p = 0.02), lathosterol (0.93 (0.87; 0.99), p = 0.02), and stigmasterol (0.51 (0.29; 0.91), p = 0.02) in breast milk sampled one-month postpartum. None of the sterols were associated with wheeze in the first two years of life. The odds of allergic sensitization at age two were lower with higher concentrations of campesterol in breast milk (OR (95%CI): 0.81 (0.70; 0.95), p = 0.01). In conclusion, our data suggest that exposure to higher non-cholesterol sterol concentrations in breast milk may indeed be associated with the prevention of allergic outcomes in the first two years of life.

We evaluated oxyphytosterol (OPS) concentrations in plasma and various tissues of two genetically modified mouse models with either increased cholesterol (apoE KO mice) or increased cholesterol and plant sterol (PS) concentrations (apoExABCG8 dKO mice). Sixteen female apoE KO and 16 dKO mice followed the same standard, low OPS-chow diet. Animals were euthanized at 36 weeks to measure PS and OPS concentrations in plasma, brain, liver and aortic tissue. Cholesterol and oxysterol (OS) concentrations were analyzed as reference for sterol oxidation in general. Plasma campesterol (24.1 ± 4.3 vs. 11.8 ± 3.0 mg/dL) and sitosterol (67.4 ± 12.7 vs. 4.9 ± 1.1 mg/dL) concentrations were severely elevated in the dKO compared to the apoE KO mice (p < 0.001). Also, in aortic and brain tissue, PS levels were significantly elevated in dKO. However, plasma, aortic and brain OPS concentrations were comparable or even lower in the dKO mice. In contrast, in liver tissue, both PS and OPS concentrations were severely elevated in the dKO compared to apoE KO mice (sum OPS: 7.4 ± 1.6 vs. 4.1 ± 0.8 ng/mg, p < 0.001). OS concentrations followed cholesterol concentrations in plasma and all tissues suggesting ubiquitous oxidation. Despite severely elevated PS concentrations, OPS concentrations were only elevated in liver tissue, suggesting that OPS are primarily formed in the liver and plasma concentrations originate from hepatic spill-over into the circulation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Improving brain insulin sensitivity may be a promising approach in the prevention and treatment of metabolic and cognitive diseases. Our aim was to investigate acute effects of inorganic nitrate on regional cerebral blood flow (CBF) responses to intranasal insulin in abdominally obese men., Methods: Eighteen apparently healthy men, aged 18-60 years and with a waist circumference ≥ 102 cm, participated in a randomized, double-blind, placebo-controlled cross-over trial. The study consisted of two test days separated by at least one week. Men received in random order a drink providing 10 mmol (i.e., 625 mg nitrate) potassium nitrate or an isomolar placebo drink with potassium chloride. Brain insulin action was assessed 120-150 min after the drinks by quantifying acute effects of nasal insulin on regional CBF using arterial spin labeling Magnetic Resonance Imaging. Glucose and insulin concentrations were measured at regular intervals, while blood pressure was determined fasted and at 240 min., Results: Inorganic nitrate intake increased regional insulin action in five brain clusters. The two largest clusters were located in the right temporal lobe (ΔCBF: 7.0 ± 3.8 mL/100 g/min, volume: 5296 mm 3 , P < 0.001; and ΔCBF: 6.5 ± 4.3 mL/100 g/min, volume: 3592 mm 3 , P < 0.001), while two other cortical clusters were part of the right frontal (ΔCBF: 9.0 ± 6.0 mL/100 g/min, volume: 1096 mm 3 , P = 0.007) and the left parietal lobe (ΔCBF: 6.1 ± 4.3 mL/100 g/min, volume: 1024 mm 3 , P = 0.012). One subcortical cluster was located in the striatum (ΔCBF: 5.9 ± 3.2 mL/100 g/min, volume: 1792 mm 3 , P < 0.001). No effects of nitrate were observed on CBF before administration. Following nitrate intake, circulating nitrate plus nitrite concentrations increased over time (P = 0.003), but insulin and glucose concentrations and blood pressure did not change., Conclusion: Acute inorganic nitrate intake may improve regional brain insulin action in abdominally obese men. These regions are involved in the regulation of different metabolic and cognitive processes. The trial was registered on January 6th, 2021 at ClinicalTrials.gov as NCT04700241., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Scope: The drug fenofibrate and dietary fish oils can effectively lower circulating triglyceride (TG) concentrations. However, a detailed comparative analysis of the effects on the plasma metabolome is missing., Methods and Results: Twenty overweight and obese subjects participate in a double-blind, cross-over intervention trial and receive in a random order 3.7 g day -1 n-3 fatty acids, 200 mg fenofibrate, or placebo treatment for 6 weeks. Four hundred twenty plasma metabolites are measured via gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Among the treatments, 237 metabolites are significantly different, of which 22 metabolites change in the same direction by fish oil and fenofibrate, including a decrease in several saturated TG-species. Fenofibrate additionally changes 33 metabolites, including a decrease in total cholesterol, and total lysophosphatidylcholine (LPC), whereas 54 metabolites are changed by fish oil, including an increase in unsaturated TG-, LPC-, phosphatidylcholine-, and cholesterol ester-species. All q < 0.05., Conclusion: Fenofibrate and fish oil reduce several saturated TG-species markedly. These reductions have been associated with a decreased risk for developing cardiovascular disease (CVD). Interestingly, fish oil consumption increases several unsaturated lipid species, which have also been associated with a reduced CVD risk. Altogether, this points towards the power of fish oil to change the plasma lipid metabolome in a potentially beneficial way., (© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Objectives: Brain-derived neurotrophic factor (BDNF) plays a role in cognition and metabolism. Specific nutrients can affect fasting BDNF concentrations, which are potentially mediated by insulin and/or glucose. Since macronutrients trigger each a different insulin and glucose response, we examined postprandial effects of meals rich in fat, carbohydrates, or protein on BDNF concentrations. BDNF was analyzed in serum and plasma, since concentration differences can be found between matrices. Methods: Healthy overweight/obese male participants ( n = 18) participated in this randomized, double-blind, cross-over trial consisting of three test days with 1 week wash-out periods. Either a high-fat (En% fat, carbohydrates, protein: 52.3, 39.2, 8.0), high-carbohydrate (En% 9.6, 81.5, 8.6) or high-protein meal (En% 10.6, 51.5, 36.9) was consumed on each test day. BDNF concentrations were measured after 0, 60, and 240 min. Glucose and insulin concentrations were measured after 0, 15, 30, 45, 60, 90, 120, and 240 min. Results: BDNF concentrations were higher in serum compared with plasma ( P < 0.001). Postprandial BDNF concentrations in serum decreased significantly after the high-fat ( P = 0.013) and high-carbohydrate meals ( P = 0.040), and showed a trend after the high-protein meal ( P = 0.076). No differences were found between meals ( P = 0.66). Postprandial BDNF concentrations measured in plasma did not significantly change after the different meals ( P = 0.47). As total area under the curve (AUC) for glucose was significantly higher after the high-carbohydrate meal compared with the high-fat ( P = 0.003) and high-protein meals ( P < 0.001), and the total AUC for insulin was higher after the high-carbohydrate ( P < 0.001) and high-protein meals ( P < 0.001) compared with the high-fat meal, it seems that acute changes in glucose and insulin do not affect postprandial BDNF concentrations. However, after the high-protein meal, the higher total AUC for glucose correlated with lower serum BDNF concentrations, and a higher maximal increase in glucose correlated with a lower maximal increase in plasma BDNF concentrations. There were no correlations with insulin concentrations after either meal. Conclusion: Serum BDNF concentrations were higher than plasma concentrations. Since postprandial BDNF responses were not different between the meals, we conclude that there is no role for insulin or glucose in regulating postprandial BDNF concentrations. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03139890]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gravesteijn, Mensink, Smeets and Plat.)

L-citrulline may improve non-invasive vascular function and cardiometabolic risk markers through increases in L-arginine bioavailability and nitric oxide synthesis. A meta-analysis of randomized controlled trials (RCTs) was performed to examine longer-term and postprandial effects of L-citrulline supplementation and watermelon consumption on these markers for cardiovascular disease in adults. Summary estimates of weighted mean differences (WMDs) in vascular function and cardiometabolic risk markers with accompanying 95% confidence intervals (CIs) were calculated using random or fixed-effect meta-analyses. Seventeen RCTs were included involving an L-citrulline intervention, of which six studied postprandial and twelve longer-term effects. Five studies investigated longer-term effects of watermelon consumption and five assessed effects during the postprandial phase. Longer-term L-citrulline supplementation improved brachial artery flow-mediated vasodilation (FMD) by 0.9 %-point (95 % CI: 0.7 to 1.1, P < 0.001). Longer-term watermelon consumption improved pulse wave velocity by 0.9 m/s (95% CI: 0.1 to 1.5, P < 0.001), while effects on FMD were not studied. No postprandial effects on vascular function markers were found. Postprandial glucose concentrations decreased by 0.6 mmol/L (95% CI: 0.4 to 0.7, P < 0.001) following watermelon consumption, but no other longer-term or postprandial effects were observed on cardiometabolic risk markers. To conclude, longer-term L-citrulline supplementation and watermelon consumption may improve vascular function, suggesting a potential mechanism by which increased L-citrulline intake beneficially affects cardiovascular health outcomes in adults. No effects on postprandial vascular function markers were found, while more research is needed to investigate effects of L-citrulline and watermelon on risk markers related to cardiometabolic health.

Background: Effects of soy foods on cerebral blood flow (CBF)-a marker of cerebrovascular function-may contribute to the beneficial effects of plant-based diets on cognitive performance., Objectives: We aimed to investigate longer-term effects of soy nut consumption on CBF in older adults. Changes in 3 different domains of cognitive performance were also studied., Methods: Twenty-three healthy participants (age: 60-70 y; BMI: 20-30 kg/m2) participated in a randomized, controlled, single-blinded crossover trial with an intervention (67 g/d of soy nuts providing ∼25.5 g protein and 174 mg isoflavones) and control period (no nuts) of 16 wk, separated by an 8-wk washout period. Adults followed the Dutch food-based dietary guidelines. At the end of each period, CBF was assessed with arterial spin labeling MRI. Psychomotor speed, executive function, and memory were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB)., Results: No serious adverse events were reported, and soy nut intake was well tolerated. Body weights remained stable during the study. Serum isoflavone concentrations increased (daidzein mean difference ± SD: 128 ± 113 ng/mL, P < 0.001; genistein: 454 ± 256 ng/mL, P < 0.001), indicating excellent compliance. Regional CBF increased in 4 brain clusters located in the left occipital and temporal lobes (mean ± SD increase: 11.1 ± 12.4 mL · 100 g-1 · min-1, volume: 11,296 mm3, P < 0.001), bilateral occipital lobe (12.1 ± 15.0 mL · 100 g-1 · min-1, volume: 2632 mm3, P = 0.002), right occipital and parietal lobes (12.7 ± 14.3 mL · 100 g-1 · min-1, volume: 2280 mm3, P = 0.005), and left frontal lobe (12.4 ± 14.5 mL · 100 g-1 · min-1, volume: 2120 mm3, P = 0.009) which is part of the ventral network. These 4 regions are involved in psychomotor speed performance, which improved as the movement time reduced by (mean ± SD) 20 ± 37 ms (P = 0.005). Executive function and memory did not change., Conclusions: Longer-term soy nut consumption may improve cerebrovascular function of older adults, because regional CBF increased. Effects may underlie observed improvements in psychomotor speed.This trial was registered at clinicaltrials.gov as NCT03627637., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)