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Introduction: Brain insulin resistance is an important hallmark of age-related conditions, including type 2 diabetes (T2D) and dementia. This systematic review summarized effects of cerebral blood flow (CBF) responses to intranasal insulin to assess brain insulin sensitivity in healthy and diseased populations. We also explored relationships between changes in brain insulin sensitivity and cognitive performance. Methods: A systemic literature search (PROSPERO: CRD42022309770) identified 58 randomized, placebo-controlled trials (RCTs) that investigated effects of intranasal insulin on (regional) CBF, cognitive performance, and systemic spill-over in adults. Results: Acute intranasal insulin did not affect whole-brain CBF in healthy adults, but increased regional CBF of the inferior frontal gyrus, dorsal striatum, and insular cortex, and reduced CBF around the middle frontal gyrus and hypothalamus. Obese adults showed increased CBF responses following internasal insulin for the middle frontal gyrus but decreased CBF for hypothalamic and cortico-limbic regions. Furthermore, increased CBF responses were reported for the insular cortex in T2D patients and for occipital and thalamic regions in older adults. The spray also improved memory and executive function, but a causal relation with regional CBF still needs to be established. Finally, intranasal insulin resulted in only a small amount of systemic spill-over, which is unlikely to have an impact on the observed findings. Conclusions: Region-specific changes in CBF after intranasal insulin administration were affected by obesity, T2D, and normal aging, indicating altered brain insulin sensitivity. Future RCTs should investigate longer-term effects of intranasal insulin and explore potential associations between effects on CBF and cognitive performance.

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.

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.

Little is known of the impact of individual saturated fatty acids (SFAs) and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review (POSPERO registration: CRD42020084241) 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 at least 14 days on one or more CMD risk markers in humans. Searches of PubMed, Embase, Scopus and Cochrane CENTRAL databases on 14th February 2021 identified 44 RCTs conducted in participants aged 39.9y (SD 15.2). 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 at least three similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in low-density lipoprotein cholesterol concentrations after the replacement of palmitic acid (C16:0) with UFA (-0.36 mmol/L, 95%CI [-0.50, -0.21], I2 = 96.0%, n = 18 RCTs) or oleic acid (C18:1) (-0.16 mmol/L, 95% CI [-0.28, -0.03], I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apolipoprotein B concentrations. No effects on other CMD risk markers, including high-density lipoprotein cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid with UFA on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFA on lipid biomarkers is aligned with current public health recommendations. However, due to the high heterogeneity and limited studies, relationships between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs.

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 randomised controlled trials (RCT) was performed to examine longer-term and postprandial effects of l-citrulline supplementation and watermelon consumption on these markers for CVD in adults. Summary estimates of weighted mean differences in vascular function and cardiometabolic risk markers with accompanying 95 % CI were calculated using random or fixed-effect meta-analyses. Seventeen RCT 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, 1·1, P < 0·001). Longer-term watermelon consumption improved pulse wave velocity by 0·9 m/s (95 % CI 0·1, 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, 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 the 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/m(2)) participated in a randomized, controlled, single-blinded crossover trial with an intervention (67 g/d of soy nuts providing similar to 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 center dot 100 g(-1) center dot min(-1), volume: 11,296 mm(3), P < 0.001), bilateral occipital lobe (12.1 +/- 15.0 mL center dot 100 g(-1) center dot min(-1), volume: 2632 mm(3), P = 0.002), right occipital and parietal lobes (12.7 +/- 14.3 mL center dot 100 g(-1) center dot min(-1), volume: 2280 mm(3), P = 0.005), and left frontal lobe (12.4 +/- 14.5 mL center dot 100 g(-1) center dot min(-1), volume: 2120 mm(3), 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.

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.

Introduction: L-arginine supplementation may improve vascular endothelial function. As tree nuts and groundnuts are a source of the amino acid L-arginine, we performed a meta-analysis of human ran-domized controlled trials (RCTs) to compare effects of tree nut and groundnut consumption with those of L-arginine supplementation on fasting and postprandial endothelial function as assessed by flow-mediated vasodilation of the brachial artery (FMD).Methods: Summary estimates of weighted mean differences (WMDs) in FMD and 95% confidence in-tervals (CIs) were calculated using random-effect meta-analyses.Results: A total of thirteen RCTs focusing on tree nut and groundnut consumption and nineteen RCTs investigating effects of L-arginine supplementation were included. Longer-term consumption of tree nuts and groundnuts increased fasting FMD by 1.09 %-point (PP) (95% CI: 0.49, 1.69, P < 0.001; I-2: 76.7%, P < 0.001), while L-arginine supplementation (daily range: 3-21 g) increased fasting FMD by 0.53 PP (95% CI: 0.12, 0.93; P = 0.012; I-2: 91.6%, P < 0.001). Effects between treatments were not statistically different (P = 0.31). Tree nut and groundnut consumption did not affect postprandial FMD responses (1.25 PP, 95% CI: -0.31, 2.81, P = 0.12; I-2: 91.4%, P < 0.001), whereas L-arginine supplementation (range: 3-15 g) improved FMD during the postprandial phase by 2.02 PP (95% CI: 0.92, 3.13, P < 0.001; I-2: 99.1%, P < 0.001). However, treatment effects did not differ significantly (P = 0.60). Overall, these results derive from high-quality evidence.Conclusion: Longer-term consumption of tree nuts and groundnuts, as well as L-arginine supplementa-tion did improve fasting endothelial function, as assessed by FMD. However, the positive effects of tree nuts and groundnuts could not be fully explained by the amount of L-arginine in these nuts. Only L-arginine supplementation did improve postprandial FMD, but effects were not different from those of tree nuts and groundnuts. Future studies should focus on the identifications of the bioactive nutrients in tree nuts and groundnuts and mechanistic pathways behind differences in postprandial and longer-term fasting changes in FMD. (c) 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Objective Increasing magnesium intake might reduce the risk of cardiovascular disease (CVD). Whether potential effects on cortisol contribute to these beneficial effects on cardiovascular health remains unclear. We therefore studied effects of long-term oral magnesium supplementation on glucocorticoid metabolism, specifically on the excretion of urinary cortisol, cortisone and their metabolites, as well as on the ratios reflecting enzymatic activity of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs) and A-ring reductases.Design A post-hoc analysis of a randomized trial with allocation to a magnesium supplement (350 mg/day) or a placebo for 24-week.Patients Forty-nine overweight men and women, aged between 45 and 70 years.Measurements Cortisol, cortisone and their metabolites (tetrahydrocortisol [THF], allo-tetrahydrocortisol [allo-THF] and tetrahydrocortisone [THE]) were measured in 24-h urine samples. Enzymatic activities of 11 beta-HSD overall and of 11 beta-HSD type 2 were estimated as the urinary (THF + allo-THF [THFs])/THE and cortisol/cortisone ratios, respectively. A-ring reductase activity was assessed by ratios of THF/allo-THF, allo-THF/cortisol, THF/cortisol and THE/cortisone.Results After 24-week, urinary cortisol excretion was decreased in the magnesium group as compared with the placebo group (-32 nmol/24-h, 95% CI: -59; -5 nmol/24-h, p = .021). Ratios of THFs/THE and cortisol/cortisone were decreased following magnesium supplementation by 0.09 (95% CI: 0.02; 0.17, p = .018) and 0.10 (95% CI: 0.03; 0.17, p = .005), respectively. No effects were observed on A-ring reductase activity.Conclusions We observed a beneficial effect of magnesium supplementation towards a lower 24-h urinary cortisol excretion together with an increased activity of 11 beta-HSD type 2. Our findings may provide another potential mechanism by which increased magnesium intake lowers CVD risk (ClinicalTrials.gov identifier: NCT02235805).

Aims: Dicarbonyl compounds contribute to the formation of advanced glycation endproducts (AGEs) and the development of insulin resistance and vascular complications. Dicarbonyl stress may already be detrimental in obesity. We evaluated whether diet-induced weight loss can effectively reverse dicarbonyl stress in abdominally obese men.Materials and methods: Plasma samples were collected from lean (n = 25) and abdominally obese men (n = 52) in the fasting state, and during a mixed meal test (MMT). Abdominally obese men were randomized to 8 weeks of dietary weight loss or habitual diet, followed by a second MMT. The a-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) and AGEs were measured by UPLC-MS/ MS. Skin autofluorescence (SAF) was measured using the AGE reader. T-tests were used for the crosssectional analysis and ANCOVA to assess the treatment effect.Results: Postprandial glucose, MGO and 3-DG concentrations were higher in obese men as compared to lean men (p < 0.05 for all). Fasting dicarbonyls, AGEs, and SAF were not different between lean and obese men. After the weight loss intervention, fasting MGO levels tended to decrease by 25 nmol/L (95%-CI:-51-0.5; p = 0.054). Postprandial dicarbonyls were decreased after weight loss as compared to the control group: iAUC of MGO decreased by 57% (5280 nmol/L.min; 95%-CI: 33-10526; p = 0.049), of GO by 66% (11,329 nmol/L.min; 95%-CI: 495-22162; p = 0.041), and of 3-DG by 45% (20,175 nmol/L.min; 95%-CI: 5351-35000; p = 0.009). AGEs and SAF did not change significantly after weight loss.Conclusion: Abdominal obesity is characterized by increased postprandial dicarbonyl stress, which can be reduced by a weight loss intervention. (C) 2021 The Authors. Published by Elsevier Ltd.

Effects of weight loss on postprandial vascular function have not been studied so far. We therefore examined (i) effects of diet-induced weight loss on postprandial changes in various vascular function markers after consumption of a mixed meal and (ii) differences between normal-weight and abdominally obese men of comparable age at baseline and after weight loss.Fifty-four apparently healthy abdominally obese (waist circumference: 102-110 cm) and 25 normal-weight men (waist circumference:94 cm) participated. The abdominally obese men were randomly allocated to a diet-induced weight-loss program or a no-weight loss control group. Men assigned to the weight-loss program followed a calorie-restricted diet for six weeks targeting a waist circumference of less than 102 cm, followed by a weight-maintenance period for two weeks. The control group maintained their habitual diet and physical activity levels. Measurements were performed before and two hours after consumption of the test meal consisting of two muffins (containing 56.6 g fat) and 300 mL low-fat milk.The mean weight loss was 10.3 kg in the weight-loss compared with the control group. The postprandial change in flow-mediated vasodilation of the brachial artery (FMD) was significantly higher at baseline in normal-weight as compared with the postprandial change in abdominally obese men (1.89 ± 2.52 versus 0.48 ± 2.50 percentage points; P = 0.027). However, no differences in postprandial changes were observed in the abdominally obese men after weight loss compared with the control treatment. Also, weight reduction did not affect postprandial changes in carotid-to-femoral pulse wave velocity, retinal microvascular caliber properties, or plasma markers of microvascular endothelial function. Even though postprandial increases in triacylglycerol (P = 0.028), insulin (P = 0.029) and C-peptide concentrations (P 0.001) were reduced in the abdominally obese men following weight loss, postprandial changes in FMD at the end of the weight-loss treatment were still more unfavorable as compared with those observed in normal-weight individuals.In this trial with abdominally obese men, we did not find effects of diet-induced weight loss on postprandial changes in vascular endothelial function, arterial stiffness and markers of microvascular function. This trial was registered on ClinicalTrials.gov under study number NCT01675401.

BACKGROUND: Only a limited number of studies have examined the vascular and postprandial effects of α-linolenic acid (ALA, C18:3n-3). Therefore, we performed a well-controlled trial focusing specifically on the effects of ALA on vascular function and metabolic risk markers during the fasting and postprandial phase in untreated (pre-)hypertensive individuals.METHODS: In a double-blind randomized, placebo-controlled parallel study, 59 overweight and obese adults (40 men and 19 women, aged 60 ± 8 years) with a high-normal blood pressure or mild (stage I) hypertension consumed daily either 10 g of refined cold-pressed flaxseed oil, providing 4.7 g ALA (n = 29), or 10 g of high-oleic sunflower (control) oil (n = 30) for 12 weeks.RESULTS: As compared with the high-oleic oil control, intake of flaxseed oil did not change brachial artery flow-mediated vasodilation, carotid-to-femoral pulse wave velocity, retinal microvascular calibers and plasma markers of microvascular endothelial function during the fasting and postprandial phase. Fasting plasma concentrations of free fatty acid (FFA) and TNF-α decreased by 58 μmol/L (P = 0.02) and 0.14 pg/mL (P = 0.03), respectively. No differences were found in other fasting markers of lipid and glucose metabolism, and low-grade systemic inflammation. In addition, dietary ALA did not affect postprandial changes in glucose, insulin, triacylglycerol, FFA and plasma inflammatory markers after meal intake.CONCLUSION: A high intake of ALA, about 3-5 times the recommended daily intake, for 12 weeks decreased fasting FFA and TNF-α plasma concentrations. No effects were found on other metabolic risk markers and vascular function during the fasting and postprandial phase in untreated high-normal and stage I hypertensive individuals.

Purpose Well-designed trials comparing side-by-side effects of macronutrients on postprandial endothelial function are missing. Therefore, we investigated under well-controlled and isocaloric condition effects of fat, carbohydrates, and protein on postprandial endothelial function as assessed by brachial artery flow-mediated vasodilation (FMD), an important non-invasive technique to assess endothelial function. Methods Eighteen apparently healthy overweight and slightly obese men (BMI 26.0–35.0 kg/m2) completed this randomized, double-blinded, cross-over trial. The study consisted of three test days each separated by a wash-out period of at least 1 week. After an overnight fast, men received an isocaloric meal providing 3987 kJ (953 kcal) that was either high in dietary fat (En% fat [F]/carbohydrates [C]/protein [P]: 52.3, 39.2, 8.0), carbohydrates (En% F/C/P: 9.6, 81.5, 8.6), or protein (En% F/C/P: 10.6, 51.5, 36.9). Fasting and 2-h postprandial FMD responses were measured. Results A postprandial decrease of 1.2% point in FMD was observed after the high-protein meal (P = 0.015). However, postprandial changes did not differ between meals (P = 0.45). An increase in baseline brachial artery diameters was observed after the high-protein meal (P P = 0.020). A meal*time interaction was found for plasma glucose concentrations, with the most pronounced increases after the high-carbohydrate meal at T15, T30, T60, and T90 (P . A significant time and meal (P P = 0.06) was found for serum insulin concentrations. Increases in serum triacylglycerol concentrations did not differ between meals (P = 0.014). Conclusion Macronutrients did not differently affect postprandial endothelial function in apparently healthy overweight and slightly obese men. Trial registration Trial registration number (ClinicalTrials.gov) NCT03139890 in May 2017

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.

OBJECTIVES: Soy foods may contribute to the beneficial effects of plant-based diets on cardiovascular disease (CVD) risk. However, their effects on vascular function have hardly been investigated. The objective was to investigate if longer-term soy nut consumption improves vascular function and cardiometabolic health in older adults. METHODS: Twenty-three apparently healthy participants (60–70 years; BMI between 20–30 kg/m(2)) participated in a randomized, controlled, single-blinded cross-over trial with an intervention (67 g of soy nuts daily providing 25.5 g soy protein) and control period (no nuts) of 16 weeks, separated by eight weeks wash-out. Volunteers followed the Dutch food-based dietary guidelines. At baseline and at 8 and 16 weeks anthropometric measurements and fasting blood samples were collected. Markers of vascular function (i.e., endothelial function, arterial stiffness, and microvascular structure) were assessed at week 16. RESULTS: No serious adverse events were reported and the soy nut regime was well tolerated. Body weight remained stable. Serum isoflavone concentrations, a marker of compliance, increased after the intervention period (daidzein: 128.3 ng/mL; 95% CI: 72.6–183.9 ng/mL; P

Backgound Theobromine, a component of cocoa, may favorably affect conventional lipid-related cardiovascular risk markers, but effects on flow-mediated dilation (FMD) and other vascular function markers are not known. Objective To evaluate the effects of 4-week theobromine consumption (500 mg/day) on fasting and postprandial vascular function markers. Design In a randomized, double-blind crossover study, 44 apparently healthy overweight (N = 30) and obese (N = 14) men and women with low HDL-C concentrations, consumed daily 500 mg theobromine or placebo for 4 weeks. After 4 weeks, FMD, peripheral arterial tonometry (PAT), augmentation index (AIx), pulse wave velocity (PWV), blood pressure (BP) and retinal microvasculature measurements were performed. These measurements were carried out under fasting conditions and 2.5 h after a high-fat mixed meal challenge. Results 4-week theobromine consumption did not change fasting vascular function markers, except for a decrease in central AIx (cAIx, − 1.7 pp, P = 0.037) and a trend towards smaller venular calibers (− 2 µm, P = 0.074). Consuming a high-fat mixed meal decreased FMD (0.89 pp, P = 0.002), reactive hyperemia index (RHI, − 0.30, P

OBJECTIVES: Effects of plant-based diets on cerebral blood flow (CBF), which is a physiological marker of cerebrovascular function, have hardly been studied and may contribute to the beneficial effects of these diets on cognitive performance. Therefore, the primary objective of this study was to investigate longer-term effects of soy nut consumption on CBF in older men and women. Changes in cognitive performance were also studied. METHODS: A randomized, controlled, cross-over trial was performed with a sixteen-week intervention period, separated by a wash-out period of eight weeks. Twenty-three males and females, aged 64 ± 3 (mean ± SD) years and with a BMI of 25.9 ± 2.7 kg/m(2), started with the soy intervention period (67 g of soy nuts daily providing 25.5 g soy protein) or control period (no nuts). The two periods were separated by a wash-out period of eight weeks. At the end of each period, CBF was assessed with arterial spin labeling magnetic resonance imaging. Cognitive performance was assessed in the main cognitive domains using well-validated CANTAB tests. RESULTS: Serum isoflavone concentrations significantly increased after the soy intervention (daidzein Δ 133 ± 113 ng/mL, P

Supplementation with anthocyanins, which are a type of flavonoids mainly found in various berries, is hypothesized to be a promising approach to lower the risk of developing cognitive decline. The aim of this systematic review was to provide a comprehensive overview of dietary intervention trials describing effects of berry anthocyanins on cognitive performance in humans, while also addressing potential underlying mechanisms. A total of 1197 articles were identified through a systematic search, and 49 studies reporting effects on cognitive performance (n = 18), vascular function (n = 22), or cardiometabolic risk markers (n = 32) were included. Significant improvements were observed on memory, while some of the studies also reported effects on attention and psychomotor speed or executive function. Vascular function markers such as brachial artery flow-mediated vasodilation were also affected and consistent evidence was provided for the beneficial effects of berry anthocyanins on endothelial function. Finally, studies reported improvements in blood pressure, but effects on metabolic risk markers (e.g. carbohydrate and lipid metabolism) were less consistent. In conclusion, this review provides evidence for the beneficial effects of berry anthocyanins on cognitive performance as memory improved. Whether observed anthocyanin-induced improvements in vascular function and blood pressure underlie beneficial effects on cognitive performance warrants further study.

Background Increased physical activity is inversely related to the risk to develop cardiovascular disease (CVD). In a recent systematic review, it was reported that CVD patients had an increased cholesterol absorption and a decreased synthesis as compared with control participants. As increased physical activity levels reduce CVD risk, we hypothesized that exercise training will reduce cholesterol absorption and increase endogenous cholesterol synthesis in older overweight and obese men. Methods A randomized, controlled, crossover trial was performed. Seventeen apparently healthy older overweight and obese men were randomized to start with an aerobic exercise or no-exercise control period for 8 weeks, separated by 12 weeks washout. Fasting serum total cholesterol (TC) and non-cholesterol sterol concentrations were measured at baseline, and after 4 and 8 weeks. Results The aerobic exercise program did not affect serum TC concentrations. In addition, exercise did not affect TC-standardized serum concentrations of sitosterol and cholestanol that are markers for cholesterol absorption. However, a trend for reduced TC-standardized campesterol concentrations, which is another validated marker for cholesterol absorption, was observed as compared with control. Lathosterol concentrations, reflecting cholesterol synthesis, did not differ between both periods. Conclusions Aerobic exercise training for 8 weeks did not lower serum TC concentrations in older overweight and obese men, but a trend towards a decrease in the cholesterol absorption marker campesterol was found. The cholesterol synthesis marker lathosterol did not change. Trial registration posted on www.clinicaltrials.gov as NCT03272061 on 7 September 2017.

Mild cold acclimation for 10 days has been previously shown to markedly improve insulin sensitivity in patients with type 2 diabetes. Here we show in a single-arm intervention study (Trialregister.nl ID: NL4469/NTR5711) in nine patients with type 2 diabetes that ten days of mild cold acclimation (16–17 °C) in which observable, overt shivering was prevented, does not result in improved insulin sensitivity, postprandial glucose and lipid metabolism or intrahepatic lipid content and only results in mild effects on overnight fasted fat oxidation, postprandial energy expenditure and aortic augmentation index. The lack of marked metabolic effects in this study is associated with a lack of self-reported shivering and a lack of upregulation of gene expression of muscle activation or muscle contraction pathways in skeletal muscle and suggests that some form of muscle contraction is needed for beneficial effects of mild cold acclimation., Cold acclimation has been shown to have beneficial metabolic effects, including improved insulin sensitivity in patients with type 2 diabetes. Here the authors show that a mild cold acclimation regiment during which overt shivering was prevented did not result in improved insulin sensitivity in a small group of patients with type 2 diabetes.

Cognitive decline is associated with lifestyle-related factors such as overweight, blood pressure, and dietary composition. Studies have reported beneficial effects of dietary anthocyanins on cognition in older adults and children. However, the effect of anthocyanin-rich Aronia melanocarpa extract (AME) on cognition is unknown. Therefore, this study aimed to determine the effect of long-term supplementation with AME on cognitive performance, mood, and vascular function in healthy, middle-aged, overweight adults. In a randomized double-blind placebo-controlled parallel study, 101 participants either consumed 90 mg AME, 150 mg AME, or placebo for 24 weeks. The grooved pegboard test, number cross-out test, and Stroop test were performed as measures for psychomotor speed, attention, and cognitive flexibility. Mood was evaluated with a visual analogue scale, serum brain-derived neurotrophic factor (BDNF) was determined, and vascular function was assessed by carotid ultrasounds and blood pressure measurements. AME improved psychomotor speed compared to placebo (90 mg AME: change = &minus, 3.37, p = 0.009). Furthermore, 150 mg AME decreased brachial diastolic blood pressure compared to 90 mg AME (change = 2.44, p = 0.011), but not compared to placebo. Attention, cognitive flexibility, BDNF, and other vascular parameters were not affected. In conclusion, AME supplementation showed an indication of beneficial effects on cognitive performance and blood pressure in individuals at risk of cognitive decline.

An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 ± 5.9 (mean ± SD) years, body mass index (BMI) 28.9 ± 4.0 kg/m2) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n = 20) or moderate protein (MP, n = 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol.

Context: Impaired insulin-mediated muscle microvascular recruitment (IMMR) may add to the development of insulin resistance and hypertension. Increased aldosterone levels have been linked to these obesity-related complications in severely to morbidly obese individuals and to impaired microvascular function in experimental studies.Objectives: To investigate whether aldosterone levels are associated with IMMR, insulin sensitivity, and blood pressure in lean and moderately abdominally obese men, and to study the effect of weight loss.Design, Setting, Participants, Intervention, Main Outcome Measures: In 25 lean and 53 abdominally obese men, 24-hour blood pressure measurement was performed, and aldosterone levels were measured using ultra-performance liquid chromatography tandem mass spectrometry. Insulin sensitivity was assessed by determining whole-body glucose disposal during a hyperinsulinemic clamp. IMMR in forearm skeletal muscle was measured with contrast-enhanced ultrasonography. These assessments were repeated in the abdominally obese men following an 8-week weight loss or weight stable period.Results: Sodium excretion and aldosterone levels were similar in lean and abdominally obese participants, but sodium excretion was inversely associated with aldosterone concentration only in the lean individuals [lean, beta/100 mmol sodium excretion (adjusted for age and urinary potassium excretion) = -0.481 (95% confidence interval, -0.949 to -0.013); abdominally obese, beta/100 mmol sodium excretion = -0.081 (95% confidence interval, -0.433 to 0.271); P for interaction = 0.02]. Aldosterone was not associated with IMMR, insulin sensitivity, or blood pressure and was unaffected by weight loss.Conclusion: In moderately abdominally obese men, the inverse relationship between sodium excretion and aldosterone concentration is less than that in lean men but does not translate into higher aldosterone levels. The absolute aldosterone level does not explain differences in microvascular and metabolic insulin sensitivity and blood pressure between lean and moderately abdominally obese men.

Background Physical activity may attenuate age-related cognitive decline by improving cerebrovascular function. The aim of this study was therefore to investigate effects of aerobic exercise training on cerebral blood flow (CBF), which is a sensitive physiological marker of cerebrovascular function, in sedentary older men. Methods Seventeen apparently healthy men, aged 60-70 years and with a BMI between 25 and 35 kg/m2, were included in a randomized, controlled cross-over trial. Study participants were randomly allocated to a fully-supervised, progressive, aerobic exercise training or no-exercise control period for eight weeks, separated by a 12-week wash-out period. Measurements at the end of each period included aerobic fitness evaluated using peak oxygen consumption during incremental exercise (VO2peak), CBF measured with pseudo-continuous arterial spin labeling magnetic resonance imaging, and post-load glucose responses determined using an oral glucose tolerance test (OGTT). Furthermore, cognitive performance was assessed in the domains of executive function, memory, and psychomotor speed. Results VO2peak significantly increased following aerobic exercise training compared to no-exercise control by 262 ± 236 mL (P < 0.001). CBF was increased by 27% bilaterally in the frontal lobe, particularly the subcallosal and anterior cingulate gyrus (cluster volume: 1008mm3; P < 0.05), while CBF was reduced by 19% in the right medial temporal lobe, mainly temporal fusiform gyrus (cluster volume: 408mm3; P < 0.05). Mean post-load glucose concentrations determined using an OGTT decreased by 0.33 ± 0.63 mmol/L (P = 0.049). Furthermore, executive function improved as the latency of response was reduced by 5% (P = 0.034), but no changes were observed in memory or psychomotor speed. Conclusion Aerobic exercise training improves regional CBF in sedentary older men. These changes in CBF may underlie exercise-induced beneficial effects on executive function, which could be partly mediated by improvements in glucose metabolism. This clinical trial is registered on clinicaltrials.org as NCT03272061 (https://clinicaltrials.gov/ct2/show/NCT03272061).

Favorable effects of a high-protein/moderate-carbohydrate (HP/MCHO) diet after weight loss on body weight management have been shown. To extend these findings, associations between perception of hunger and satiety with endocannabinoids, and with glucagon-like peptide-1 (GLP-1) and polypeptide YY (PYY) were assessed. At approximately 34 months after weight loss, 22 female and 16 male participants (mean age 64.5 &plusmn, 5.9 years, body mass index (BMI) 28.9 &plusmn, 3.9 kg/m2) completed a 48 h respiration chamber study. Participants were fed in energy balance with a HP/MCHO diet with 25%:45%:30% or a moderate-protein/high-carbohydrate (MP/HCHO) diet with 15%:55%:30% of energy from protein:carbohydrate:fat. Endocannabinoids and related compounds, relevant postprandial hormones (GLP-1, PYY), hunger, satiety, and ad libitum food intake were assessed. HP/MCHO versus MP/HCHO reduced hunger perception. The lower decremental area under the curve (dAUC) for hunger in the HP/MCHO diet (&minus, 56.6% compared to MP, p &lt, 0.05) was associated with the higher AUC for 2-arachidonoylglycerol (2-AG) concentrations (p &lt, 0.05). Hunger was inversely associated with PYY in the HP/MCHO group (r = &minus, 0.7, p &lt, 0.01). Ad libitum food intake, homeostatic model assessment for insulin resistance (HOMA-IR) and incremental AUCs for gut peptides were not different between conditions. HP/MCHO versus MP/HCHO diet-induced reduction in hunger was present after 34 months weight maintenance in the post-obese state. HP/MCHO diet-induced decrease of hunger is suggested to interact with increased 2-AG and PYY concentrations.

Background: Epidemiologic studies have suggested a protective effect of magnesium intake on cardiovascular disease risk. However, intervention trials of magnesium supplementation on blood pressure and conventional cardiometabolic risk markers are inconsistent. Effects on vascular function markers related to cardiovascular disease risk have rarely been studied.Objective: The objective was to evaluate the effects of long-term magnesium supplementation on arterial stiffness.Design: We performed a 24-wk, randomized, double-blind, placebo controlled intervention study. Fifty-two overweight and slightly obese individuals (30 men and 22 postmenopausal women, mean +/- SD age: 62 +/- 6 y) were randomly allocated to receive either 3 times daily magnesium (3 X 117 mg or 350 mg/d) or placebo capsules. Twenty-four-hour urine collections and 24-h ambulatory blood pressure assessments were performed at the start and end of the study. Carotid-to-femoral pulse wave velocity (PWVc-f) was assessed at baseline, after 12 wk, and at week 24.Results: Serum magnesium concentrations did not differ after 12 wk but tended to increase after 24-wk magnesium supplementation compared with placebo by 0.02 mmol/L (95% CI: 0.00, 0.04 mmol/L; P = 0.09). Twenty-four-hour urinary magnesium excretion increased by 2.01 mmol (95% CI: 1.22, 2.93 mmol; P Conclusion: Our data indicate that a daily magnesium supplement of 350 mg for 24 wk in overweight and obese adults reduces arterial stiffness, as estimated by a decrease in PWVc-f, suggesting a potential mechanism by which an increased dietary magnesium intake beneficially affects cardiovascular health.

Background: Through effects on nitric oxide bioavailability, vascular endothelial function is improved after the intake of a high amount of nitrate or L-arginine, but decreased after the intake of a high-fat meal. Therefore, we compared the effects of beetroot powder with or without L-arginine on postprandial brachial artery flow-mediated vasodilation (FMD) after consumption of a high-fat mixed-meal. Methods: Eighteen abdominally obese men completed this randomized, double-blinded, cross-over trial. The study consisted of five test days, each separated by a wash-out period of at least one week. Participants received in random order, a blended meal with a control or nutritional supplement consisting of beetroot powder providing 200 mg nitrate, beetroot with 0.8 g of L-arginine, beetroot with 1.5 g of L-arginine, or 3.0 g of L-arginine. Participants then fasted and 2 h postprandial FMD measurements were performed. Results: No significant differences between meals were observed for postprandial FMD (p = 0.45) levels. However, there was a non-significant trend towards a more beneficial postprandial FMD response with the beetroot-containing meals as compared with meals without beetroot. Conclusion: This trial could not provide evidence for beneficial additive effects of a single dose of beetroot powder combined with L-arginine on postprandial endothelial function in abdominally obese men.

Background Arterial stiffness is closely related to the process of atherosclerosis, an independent cardiovascular risk factor, and predictive of future cardiovascular events and mortality. Recently, we showed that magnesium citrate supplementation results in a clinically relevant improvement of arterial stiffness. It remained unclear whether the observed effect was due to magnesium or citrate, and whether other magnesium compounds may have similar effects. Therefore, we aim to study the long-term effects of magnesium citrate, magnesium oxide and magnesium sulfate on arterial stiffness. In addition, we aim to investigate possible underlying mechanisms, including changes in blood pressure and changes in gut microbiota diversity. Methods In this randomized, double-blind, placebo-controlled trial, a total of 162 healthy overweight and slightly obese men and women will be recruited. During a 24-week intervention, individuals will be randomized to receive: magnesium citrate; magnesium oxide; magnesium sulfate (total daily dose of magnesium for each active treatment 450 mg); or placebo. The primary outcome of the study is arterial stiffness measured by the carotid–femoral pulse wave velocity (PWVc–f), which is the gold standard for quantifying arterial stiffness. Secondary outcomes are office blood pressure, measured by a continuous blood pressure monitoring device, and gut microbiota, measured in fecal samples. Measurements will be performed at baseline and at weeks 2, 12 and 24. Discussion The present study is expected to provide evidence for the effects of different available magnesium formulations (organic and inorganic) on well-established cardiovascular risk markers, including arterial stiffness and blood pressure, as well as on the human gut microbiota. As such, the study may contribute to the primary prevention of cardiovascular disease in slightly obese, but otherwise healthy, individuals. Trial registration ClinicalTrials.gov, NCT03632590. Retrospectively registered on 15 August 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3414-4) contains supplementary material, which is available to authorized users.

Context: Hepatokines have emerged as potential mediators of obesity-associated comorbidities, such as type 2 diabetes, cardiovascular disease, fractures, and central hypogonadism.Objective: To assess whether weight loss-induced changes in hepatokines are mediated by intrahepatic triglyceride (IHTG) content.Design: Cross-sectional study and randomized controlled trial.Setting: General community.Participants: Metabolically healthy, lean men (waistIntervention: Men with abdominal obesity were randomized to 8-week dietary weight loss or no weight loss.Main Outcome Measures: IHTG and serum hepatokines, that is, serum IGF1, IGF binding protein 1 (IGFBP1), SHBG, fibroblast growth factor 21 (FGF21), fetuin A, and plasma fetuin B.Results: All hepatokines, except for fetuin B, were significantly different between lean men and men with obesity. After the weight-loss intervention (-10.3 kg; 95% CI, -11.4 to-9.2), serum IGF1, IGFBP1, SHBG, and fetuin A approached the values observed in lean men. Cross-sectional associations were observed between IHTG and IGF1 (beta = -0.51; 95% CI, -0.82 to -0.20), IGFBP1 (beta = -4.2; 95% CI, -7.7 to -0.7), and FGF21 (beta = 2.1; 95% CI, 1.3 to 2.9) in lean men and men with abdominal obesity combined. Weight loss resulted in a reduction of IHTG (treatment effect, -2.2%; 95% CI, -3.4% to -1.2%) that was associated with a change in IGF1 (beta = -0.9; 95% CI, -1.3 to -0.4), IGFBP1 (beta = -0.17; 95% CI, -0.31 to -0.03), and SHBG levels (beta = -0.18; 95% CI, -0.29 to -0.07). Mediation analyses showed that only the weight loss-induced change in serum IGF1 was mediated by IHTG (mediated effect, 32.7%; 95% CI, 4.6% to 79.2%).Conclusions: Dietary weight loss has differential effects on hepatokines. This study shows that the change in serum IGF1 levels after dietary weight loss is mediated by the change in IHTG content.

Improving cerebrovascular function may be a key mechanism whereby a healthy lifestyle, of which a healthy diet combined with increased physical activity levels is a cornerstone, protects against cognitive impairments. In this respect, effects on cerebral blood flow (CBF)—a sensitive physiological marker of cerebrovascular function—are of major interest. This review summarizes the impact of specific dietary determinants and physical exercise on CBF in adults and discusses the relation between these effects with potential changes in cognitive function. A limited number of randomized controlled trials have already demonstrated the beneficial effects of an acute intake of nitrate and polyphenols on CBF, but evidence for a relationship between these effects as well as improvements in cognitive functioning is limited. Moreover, long-term trans-resveratrol supplementation has been shown to increase CBF in populations at increased risk of accelerated cognitive decline. Long-term supplementation of n-3 long-chain polyunsaturated fatty acids may also increase CBF, but related effects on cognitive performance have not yet been found. Significant decreases in cerebral perfusion were observed by commonly consumed amounts of caffeine, while alcohol intake was shown to increase CBF in a dose-dependent way. However, the long-term effects are not clear. Finally, long-term exercise training may be a promising approach to improve CBF, as increases in perfusion may contribute to the beneficial effects on cognitive functioning observed following increased physical activity levels.

Introduction The response to dietary challenges has been proposed as a more accurate measure of metabolic health than static measurements performed in the fasted state. This has prompted many groups to explore the potential of dietary challenge tests for assessment of diet and lifestyle induced shifts in metabolic phenotype. Objectives We examined whether the response to a mixed-meal challenge could provide a readout for a weight loss (WL)-induced phenotype shift in abdominally obese male subjects. The underlying assumption of a mixed meal challenge is that it triggers all aspects of phenotypic flexibility and provokes a more prolonged insulin response, possibly allowing for better differentiation between individuals. Methods Abdominally obese men (n = 29, BMI = 30.3 ± 2.4 kg/m2) received a mixed-meal challenge prior to and after an 8-week WL or no-WL control intervention. Lean subjects (n = 15, BMI = 23.0 ± 2.0 kg/m2) only received the mixed meal challenge at baseline to have a benchmark for WL-induced phenotype shifts. Results Levels of several plasma metabolites were significantly different between lean and abdominally obese at baseline as well as during postprandial metabolic responses. Genes related to oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) were expressed at higher levels in abdominally obese subjects as compared to lean subjects at fasting, which was partially reverted after WL. The impact of WL on the postprandial response was modest, both at the metabolic and gene expression level in PBMCs. Conclusion We conclude that mixed-meal challenges are not necessarily superior to measurements in the fasted state to assess metabolic health. Furthermore, the mechanisms accounting for the observed differences between lean and abdominally obese in the fasted state are different from those underlying the dissimilarity observed during the postprandial response. Electronic supplementary material The online version of this article (10.1007/s11306-018-1328-x) contains supplementary material, which is available to authorized users.

The effects of fat-soluble vitamin supplementation on cardiovascular disease (CVD) risk are not clear. Therefore, we performed a meta-analysis to quantify effects of fat-soluble vitamin supplements on fasting flow-mediated vasodilation (FMD) of the brachial artery, a validated marker to assess CVD risk. Randomized placebo-controlled trials (RCTs) were identified by a systematic search till July 2014. Seven RCTs studying the effects of vitamin E supplements (range: 300 to 1800 IU per day) and nine RCTs examining the effects of vitamin D supplements, that involved, respectively, 303 and 658 adults, were included. No studies with carotenoid or vitamin K supplements were found. Vitamin E supplementation increased FMD vs. control by 2.42% (95% CI: 0.46% to 4.37%, p = 0.015). No effects of vitamin D supplementation were found (0.15%, 95% CI: −0.21% to 0.51%, p = 0.41). These effects did not depend on subject characteristics, treatment characteristics or technical aspects of the FMD measurement. However, no dose-response relationship was evident for vitamin E, statistical significance depended on one study, while the levels of supplement were far above recommended intakes. The current meta-analysis, therefore, does not provide unambiguous evidence to support the use of fat-soluble vitamin supplements to improve fasting FMD in adults.

Background Obesity is associated with vascular endothelial dysfunction. Effects of weight loss on endothelial function are however not clear. Therefore, we performed a meta-analysis to quantify effects of weight loss on flow-mediated vasodilation (FMD) of the brachial artery, a measurement of endothelial function. Methods Studies with experimental (RCTs) and quasi-experimental designs published before June 2014 were identified by a systematic search. Changes in FMD were defined as the difference between measurements before and after the study. For RCTs, changes were corrected for those in the no-weight loss control group. Summary estimates of weighted mean differences (WMDs) in FMD and 95% confidence intervals (CIs) were calculated using random-effect meta-analyses. The impact of subject characteristics, type of weight-loss treatment, and dietary composition on changes in FMD was also investigated. Results Four RCTs involving 265 subjects were included. Weight loss increased FMD vs. control by 3.29% (95% CI: 0.98–5.59%; P = 0.005; mean weight loss: 8.6 kg). A total of 1517 subjects participated in 33 studies with 49 relevant study arms. It was estimated that each 10 kg decrease in body weight increased fasting FMD by 1.11% (95% CI: 0.47–1.76%; P = 0.001). Effects were more pronounced when participants had coexisting obesity-related morbidities. Also, effects may be larger when subjects received low-fat diets or weight-reduction regimens including exercise therapy or weight-loss medication. Conclusion Weight loss significantly improves fasting FMD in adults, which is a risk marker for cardiovascular disease. Effects may depend on subject characteristics, type of weight-loss treatment, and dietary composition.

Background Induction of insulin resistance is a key pathway through which obesity increases risk of type 2 diabetes, hypertension, dyslipidemia, and cardiovascular events. Although the detrimental effects of obesity on insulin sensitivity are incompletely understood, accumulation of visceral, subcutaneous, and liver fat and impairment of insulin-induced muscle microvascular recruitment (MVR) may be involved. As these phenotypic changes often coincide in obesity, we aimed to unravel whether they independently contribute to insulin resistance and thus constitute separate targets for intervention. Methods We measured visceral (VAT) and subcutaneous adipose tissue (SAT) volumes and intrahepatic lipid (IHL) content by MRI, and whole body glucose disposal (WBGD) and MVR (using contrast-enhanced ultrasound) responses to a euglycemic insulin clamp in lean (n = 25) and abdominally obese men (n = 52). Abdominally obese men were randomized to dietary weight loss intervention or habitual diet. Results Obesity-associated increases in VAT, SAT, and IHL, along with the decrease in MVR, contributed independently to insulin resistance. Moreover, a dietary weight loss intervention reduced insulin resistance, and mediation analyses showed that decreased IHL and insulin-induced MVR, but not decreased VAT or SAT volumes, independently contributed to improved insulin resistance seen with weight loss. Conclusion Quantifying the mutually independent contributions of visceral and subcutaneous adipose tissue, intrahepatic lipid, and insulin-induced muscle microvascular recruitment reveals distinct targets for treating obesity-associated insulin resistance. Trial registration Clinicaltrials.gov NCT01675401. Funding Funding was from the Top Institute Food and Nutrition.

Long-term magnesium supplementation improves arterial stiffness, a cardiovascular disease risk marker. Effects on endothelial function may be another mechanism whereby increased magnesium intakes affect cardiovascular risk. Therefore, a 24-week, randomized, double-blind, placebo-controlled trial was performed to examine effects of magnesium supplementation on endothelial function and cardiometabolic risk markers. Fifty-two overweight and obese subjects (30 men and 22 women, age 62 ± 6 years) were randomized to receive either three times daily magnesium (total dose: 350 mg) or placebo capsules. Endothelial function was assessed at the start and at the end of the study. Cardiometabolic risk markers were measured at baseline, after 12 weeks, and at week 24. Brachial artery flow-mediated vasodilation did not change following long-term magnesium supplementation (0.49 pp; 95% CI: −0.38 to 1.36 pp; P = 0.26). Changes in reactive hyperemia index, retinal microvascular caliber and plasma markers for microvascular endothelial function (sVCAM-1, sICAM-1 and sE-selectin) were also not different. In addition, no effects on serum lipids, plasma glucose, insulin sensitivity, and low-grade systemic inflammation were observed. In conclusion, a daily magnesium supplement of 350 mg for 24 weeks does not improve endothelial function and cardiometabolic risk markers in overweight and obese middle-aged and elderly adults.