Long-term effects of an egg-protein hydrolysate on cognitive performance and brain vascular function: a double-blind randomized controlled trial in adults with elevated subjective cognitive failures.

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.

Short-term Aronia melanocarpa extract supplementation improves cognitive performance: a randomized, double-blind, placebo-controlled cross-over study in healthy young adults.

PURPOSE: Evidence on the potential beneficial effects of anthocyanin-rich foods and supplements on cognitive performance is mainly based on acute or long-term studies in older adults. However, short-term studies focusing on a younger population are lacking. Therefore, short-term effects of Aronia melanocarpa extract (AME) supplementation on cognitive performance were investigated in healthy young adults. Potential underlying mechanisms were also addressed. METHODS: A randomized, double-blind, placebo-controlled cross-over study was performed involving 35 apparently healthy young adults. Participants consumed AME (180 mg anthocyanins/day) or a placebo for 1 week, separated by at least 2 weeks of wash-out. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Furthermore, arterial stiffness (carotid-to-femoral pulse wave velocity), retinal microvascular calibers (fundus photography), and serum brain-derived neurotrophic factor (BDNF) concentrations were measured at baseline and after 1 week. RESULTS: Participants had a mean age of 25 ± 4 years and an average BMI of 23.4 ± 2.7 kg/m2. Compliance was excellent and the study product was well-tolerated. As compared to placebo, movement time was significantly reduced by 4.8% within the five-choice reaction time test after 1 week of AME supplementation (intervention effect: - 12 ms; p < 0.05). Memory and executive function did however not change. Serum BDNF concentrations were significantly higher after AME supplementation as compared to placebo (+ 5.7%; intervention effect: 1.8 ng/mL; p < 0.05). However, arterial stiffness and retinal microvascular calibers were not affected. CONCLUSION: Short-term AME supplementation beneficially affected cognitive performance as attention and psychomotor speed improved. Serum BDNF concentrations were increased, but vascular function markers were not affected. CLINICAL TRIAL REGISTRATION: The study was registered on Clinical Trials under NCT03793777 on January 4th, 2019.

Plant stanol consumption increases anti-COVID-19 antibody responses, independent of changes in serum cholesterol concentrations: a randomized controlled trial.

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.

Perspective: Peer Evaluation of Recommendations for CONSORT Guidelines for Randomized Controlled Trials in Nutrition.

Creating effective dietary guidance requires a rigorous evidence base that is predominantly developed from robust clinical trials or large-scale cohort studies, with the quality of the data available depending on the completeness and accuracy of their reporting. An international group of academics from 14 institutions in 12 different countries and on 5 continents, working on behalf of the Federation of European Nutrition Societies within its "Improving Standards in the Science of Nutrition" initiative, reviewed the Consolidated Standards of Reporting Trials (CONSORT) statement checklist as it pertains to nutrition trials. This perspective piece documents the procedure followed to gain input and consensus on the checklist previously published by this group, including its presentation and interrogation at the International Union of Nutritional Sciences International Congress of Nutrition 2022 (IUNS-ICN 22), inputs from a survey of journal editors, and its piloting on 8 nutrition trials of diverse designs. Overall, the initiative has been met with considerable enthusiasm. At IUNS-ICN 22, refinements to our proposal were elicited through a World Café method discussion with participating nutrition scientists. The contributing journal editors provided valuable insights, and the discussion led to the development of a potential tool specific to assess adherence to the proposed nutrition extension checklist. The piloting of the proposed checklist provided evidence from real-life studies that reporting of nutrition trials can be improved. This initiative aims to stimulate further discussion and development of a CONSORT-nutrition-specific extension.

Effects of Intermittent Energy Restriction Compared with Those of Continuous Energy Restriction on Body Composition and Cardiometabolic Risk Markers - A Systematic Review and Meta-Analysis of Randomized Controlled Trials in Adults.

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/m2)], 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.

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity.

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/m2) 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.

Longer-term effects of the egg-protein hydrolysate NWT-03 on arterial stiffness and cardiometabolic risk markers in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled, crossover trial.

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/m2) 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 (PWVc-r), carotid-to-femoral pulse wave velocity (PWVc-f), and central augmentation index (CAIxHR75). Moreover, cardiometabolic markers were assessed. RESULTS: Compared with control, longer-term NWT-03 supplementation did not affect fasting PWVc-r (0.1 m/s; -0.2 to 0.3; P = 0.715) or PWVc-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.

Longer-term mixed nut consumption improves brain vascular function and memory: A randomized, controlled crossover trial in older adults.

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/m2) 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.

The effects of long-term almond consumption on whole-body insulin sensitivity, postprandial glucose responses, and 48 h continuous glucose concentrations in males and females with prediabetes: a randomized controlled trial.

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.

Perspectives on the application of CONSORT guidelines to randomised controlled trials in nutrition.

PURPOSE: Reporting guidelines facilitate quality and completeness in research reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement is widely applied to dietary and nutrition trials but has no extension specific to nutrition. Evidence suggests poor reporting in nutrition research. The Federation of European Nutrition Societies led an initiative to make recommendations for a nutrition extension to the CONSORT statement towards a more robust reporting of the evidence base. METHODS: An international working group was formed of nutrition researchers from 14 institutions in 12 different countries and on five continents. Using meetings over a period of one year, we interrogated the CONSORT statement specifically for its application to report nutrition trials. RESULTS: We provide a total of 28 new nutrition-specific recommendations or emphasised recommendations for the reporting of the introduction (three), methods (twelve), results (five) and discussion (eight). We also added two additional recommendations that were not allocated under the standard CONSORT headings. CONCLUSION: We identify a need to provide guidance in addition to CONSORT to improve the quality and consistency of the reporting and propose key considerations for further development of formal guidelines for the reporting of nutrition trials. Readers are encouraged to engage in this process, provide comments and conduct specific studies to inform further work on the development of reporting guidelines for nutrition trials.

Relation between single nucleotide polymorphisms in circadian clock relevant genes and cholesterol metabolism.

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.

Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases-A German Expert Panel Statement.

Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.

A Transient Inflammatory Response Induced by Lipopolysaccharide Infusion Lowers Markers of Endogenous Cholesterol and Bile Acid Synthesis in Healthy Normocholesterolemic Young Men.

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.

Effects of the egg protein hydrolysate NWT-03 on cognitive function in men and women with the metabolic syndrome: a randomized, double-blind, placebo-controlled study.

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.

Serum Low Density Lipoprotein Cholesterol Concentration Is Not Dependent on Cholesterol Synthesis and Absorption in Healthy Humans.

Introduction. Pharmacological reduction of cholesterol (C) synthesis and C absorption lowers serum low-density lipoprotein C (LDL-C) concentrations. We questioned whether high baseline C synthesis or C absorption translates into high serum LDL-C concentrations or if there was no connection. Therefore, we studied the association between serum LDL-C and C synthesis or C absorption in healthy subjects. Methods. Three published data sets of young subjects on different diets (study 1), mildly hypercholesterolemic subjects without cardiovascular disease (study 2) and healthy controls of the Framingham study (study 3) were used. The three study populations varied in sex, age, and weight. C synthesis and C fractional absorption rate (FAR) were measured with fecal sterol balance and stable isotope techniques (studies 1 and 2). Additionally, serum lathosterol and campesterol concentrations corrected for the serum total C concentration (R_lathosterol and R_campesterol) were used as markers for hepatic C synthesis and C FAR, respectively (studies 1−3). Linear regression analysis was applied to evaluate associations between LDL-C, C synthesis, and C absorption. Results. Seventy-three, 37, and 175 subjects were included in studies 1, 2, and 3, respectively. No statistically significant associations were found between LDL-C and the measured C synthesis and C FAR, nor for R_lathosterol and R_campesterol in any of the study groups. This lack of associations was confirmed by comparing the male subjects of studies 1 and 2. Study 1 subjects had a 50% lower serum LDL-C than the study 2 subjects (p < 0.01), but not a lower C synthesis, C FAR, R-lathosterol, or R_campesterol. Conclusions. Under physiological conditions, C synthesis and C FAR are not major determinants of circulating serum LDL-C concentrations in healthy subjects. The results need to be confirmed in large-scale studies in healthy subjects and patients at risk for cardiovascular disease.

Potential for Omega-3 Fatty Acids to Protect against the Adverse Effect of Phytosterols: Comparing Laboratory Outcomes in Adult Patients on Home Parenteral Nutrition Including Different Lipid Emulsions.

BACKGROUND: the effect on liver function markers and inflammation of the different content of phytosterols in lipid emulsions (LEs) used in the parenteral nutrition (PN) regimen of adult home PN (HPN) patients is not clear. METHODS: plasma phytosterol and cytokine concentrations, fatty acid composition, liver function markers, and triglycerides were measured in 58 adult HPN patients receiving one of three different LEs (soybean oil-based: Intralipid; olive oil-based: ClinOleic; containing fish oil: SMOFLipid). RESULTS: patients receiving Intralipid had higher plasma campesterol and stigmasterol concentrations than those receiving ClinOleic or SMOFLipid. Plasma sterol concentrations were not different between patients receiving ClinOleic and SMOFLipid. Differences in plasma fatty acids reflected the fatty acid composition of the LEs. Markers of liver function did not differ among the three groups. Blood triglycerides were higher with ClinOleic than with Intralipid or SMOFLipid. Total bilirubin correlated positively with the plasma concentrations of two of the phytosterols, ALT correlated positively with one, AST with one, and GGT with three. CONCLUSIONS: liver function markers correlate with plasma plant sterol concentrations in adult HPN patients. Adult HPN patients receiving SMOFLipid are more likely to have liver function markers and triglycerides within the normal range than those receiving ClinOleic or Intralipid. The omega-3 fatty acids in SMOFLipid may act to mitigate the adverse effects of plant sterols on liver function.

Investigating microRNAs to Explain the Link between Cholesterol Metabolism and NAFLD in Humans: A Systematic Review.

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.

A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction.

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.

Effects of Individual Amino Acids on PPARα Transactivation, mTORC1 Activation, ApoA-I Transcription and pro-ApoA-I Secretion.

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.

Effects of Diet-Induced Weight Loss on Plasma Markers for Cholesterol Absorption and Synthesis: Secondary Analysis of a Randomized Trial in Abdominally Obese Men.

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.