Short term fat feeding rapidly increases plasma insulin but does not result in dyslipidaemia

Although the association between obesity and hypertension is well known, the underlying mechanism remains elusive. Previously, we have shown that 3 week fat feeding in rabbits produces greater visceral adiposity, hypertension, tachycardia and elevated renal sympathetic nerve activity compared to rabbits on a normal diet. Because hyperinsulinaemia, hyperleptinemia and dyslipidaemia are independent cardiovascular risk factors associated with hypertension we compared plasma insulin, leptin and lipid profiles in male New Zealand White rabbits fed a normal fat diet (NFD 4.3% fat, n = 11) or high fat diet (HFD 13.4% fat, n = 13) at days 1, 2, 3 and weeks 1, 2, 3 of the diet. Plasma concentrations of diacylglyceride (DG), triacylglyceride (TG), ceramide and cholesteryl esters (CE) were obtained after analysis by liquid chromatography mass spectrometry. Plasma insulin and glucose increased within the first 3 days of the diet in HFD rabbits (P <0.05) and remained elevated at week 1 (P <0.05). Blood pressure and heart rate followed a similar pattern. By contrast, in both groups, plasma leptin levels remained unchanged during the first few days (P >0.05), increasing by week 3 in fat fed animals alone (P <0.05). Concentrations of total DG, TG, CE and Ceramide at week 3 did not differ between groups (P >0.05). Our data show plasma insulin increases rapidly following consumption of a HFD and suggests that it may play a role in the rapid rise of blood pressure. Dyslipidaemia does not appear to contribute to the hypertension in this animal model

Associations of blood pressure variability and retinal arteriolar diameter in participants with type 2 diabetes

Blood pressure variability is associated with macrovascular complications and stroke, but its association with the microcirculation in type II diabetes has not been assessed. This study aimed to determine the relationship between blood pressure variability indices and retinal arteriolar diameter in non-diabetic and type II diabetes participants. Digitized retinal images were analysed to quantify arteriolar diameters in 35 non-diabetic (aged 52 ± 11 years; 49% male) and 28 type II diabetes (aged 61 ± 9 years; 50% male) participants. Blood pressure variability was derived from 24-h ambulatory blood pressure. Arteriolar diameter was positively associated with daytime rate of systolic blood pressure variation (p = 0.04) among type II diabetes participants and negatively among non-diabetics (p = 0.008; interaction p = 0.001). This finding was maintained after adjusting for age, sex, body mass index and mean daytime systolic blood pressure. These findings suggest that the blood pressure variability-related mechanisms underlying retinal vascular disease may differ between people with and without type II diabetes

Ambulatory blood pressure monitoring and morning surge in blood pressure in adult black and white South Africans

We examined whether there were differences in the circadian variation in blood pressure and the morning surge in blood pressure between black and white Africans. Clinic and ambulatory blood pressure data obtained from the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study was examined (n = 406; 49% black African). Ambulatory blood pressure readings were fitted to a six-parameter double logistic equation to determine the power and rate of the morning surge in blood pressure. Multiple linear regression analysis was used to examine differences in blood pressure between black and white participants. Clinic and ambulatory blood pressure were higher in black participants throughout the day and night. In those taking medications, blood pressure was less well controlled in black subjects. Despite the higher systolic blood pressure, the day-night difference estimated by the logistic function was similar in black and white participants. However, the rate of rise and power in the morning surge in blood pressure was lower in black participants. We conclude that black participants of the SABPA study present with higher blood pressure throughout the day and night but have a lower power of the morning surge in blood pressure due to a slower morning rate of increase. Moreover, they had an increased prevalence of undiagnosed hypertension and, in those taking medication, were less likely to have their blood pressure controlled than their white counterparts

The Gut Microbiota and Their Metabolites in Human Arterial Stiffness

Aim: Gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) have vasodilator properties in animal and human ex vivo arteries. However, the role of the gut microbiota and SCFAs in arterial stiffness in humans is still unclear. Here we aimed to determine associations between the gut microbiome, SCFA and their G-protein coupled sensing receptors (GPCRs) in relation to human arterial stiffness. / Methods: Ambulatory arterial stiffness index (AASI) was determined from ambulatory blood pressure (BP) monitoring in 69 participants from regional and metropolitan regions in Australia (55.1% women; mean, 59.8± SD, 7.26 years of age). The gut microbiome was determined by 16S rRNA sequencing, SCFA levels by gas chromatography, and GPCR expression in circulating immune cells by real-time PCR. / Results: There was no association between metrics of bacterial α and β diversity and AASI or AASI quartiles in men and women. We identified two main bacteria taxa that were associated with AASI quartiles: Lactobacillus spp. was only present in the lowest quartile, while Clostridium spp. was present in all quartiles but the lowest. AASI was positively associated with higher levels of plasma, but not faecal, butyrate. Finally, we identified that the expression of GPR43 (FFAR2) and GPR41 (FFAR3) in circulating immune cells were negatively associated with AASI. / Conclusions: Our results suggest that arterial stiffness is associated with lower levels of the metabolite-sensing receptors GPR41/GPR43 in humans, blunting its response to BP-lowering metabolites such as butyrate. The role of Lactobacillus spp. and Clostridium spp., as well as butyrate-sensing receptors GPR41/GPR43, in human arterial stiffness needs to be determined

Essential Hypertension Is Associated With Changes in Gut Microbial Metabolic Pathways A Multisite Analysis of Ambulatory Blood Pressure

Recent evidence supports a role for the gut microbiota in hypertension, but whether ambulatory blood pressure is associated with gut microbiota and their metabolites remains unclear. We characterized the function of the gut microbiota, their metabolites and receptors in untreated human hypertensive participants in Australian metropolitan and regional areas. Ambulatory blood pressure, fecal microbiome predicted from 16S rRNA gene sequencing, plasma and fecal metabolites called short-chain fatty acid, and expression of their receptors were analyzed in 70 untreated and otherwise healthy participants from metropolitan and regional communities. Most normotensives were female (66%) compared with hypertensives (35%, P<0.01), but there was no difference in age between the groups (59.2±7.7 versus 60.3±6.6 years old). Based on machine learning multivariate covariance analyses of de-noised amplicon sequence variant prevalence data, we determined that there were no significant differences in predicted gut microbiome α- and β-diversity metrics between normotensives versus essential or masked hypertensives. However, select taxa were specific to these groups, notably Acidaminococcus spp., Eubacterium fissicatena, and Muribaculaceae were higher, while Ruminococcus and Eubacterium eligens were lower in hypertensives. Importantly, normotensive and essential hypertensive cohorts could be differentiated based on gut microbiome gene pathways and metabolites. Specifically, hypertensive participants exhibited higher plasma acetate and butyrate, but their immune cells expressed reduced levels of short-chain fatty acid-activated GPR43 (G-protein coupled receptor 43). In conclusion, gut microbial diversity did not change in essential hypertension, but we observed a significant shift in microbial gene pathways. Hypertensive subjects had lower levels of GPR43, putatively blunting their response to blood pressure-lowering metabolites

Probe-caught spontaneous and deliberate mind wandering in relation to self-reported inattentive, hyperactive and impulsive traits in adults.

Research has revealed a positive relationship between types of mind wandering and ADHD at clinical and subclinical levels. However, this work did not consider the relationship between mind wandering and the core symptoms of ADHD: inattention, hyperactivity and impulsivity. Given that the DMS-V attributes mind wandering to inattention only, and that only inattention is thought to result from impairment to the executive function linked to mind wandering, the present research sought to examine this relationship in 80 undiagnosed adults. Using both standard and easy versions of the Sustained Attention to Response Task (SART) we measured both spontaneous and deliberate mind wandering. We found that spontaneous mind wandering was related to self-reported inattentive traits when the task was cognitively more challenging (standard SART). However, hyperactive and impulsive traits were related to spontaneous mind wandering independent of task difficulty. The results suggest inattentive traits are not uniquely related to mind wandering; indeed, adults with hyperactive/impulsive traits were more likely to experience mind wandering, suggesting that mind wandering might not be useful diagnostic criteria for inattention

The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase

We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop

Microbial Interventions to Control and Reduce Blood Pressure in Australia (MICRoBIA): rationale and design of a double-blinded randomised cross-over placebo controlled trial

Background: Hypertension is a prevalent chronic disease worldwide that remains poorly controlled. Recent studies support the concept that the gut microbiota is involved in the development of hypertension and that dietary fibre intake may act through the gut microbiota to lower blood pressure (BP). Resistant starch is a type of prebiotic fibre which is metabolised by commensal bacteria in the colon to produce short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate. Previous work in pre-clinical models provides strong evidence that both prebiotic fibre as well as SCFAs (i.e. postbiotics) can prevent the development of hypertension. The aim of this clinical trial is to determine if acetylated and butyrylated modified resistant starch can decrease BP of hypertensive individuals via the modulation of the gut microbiota and release of high levels of SCFAs.Methods: This is a phase IIa double-blinded, randomised, cross-over, placebo controlled trial. Participants are randomly allocated to receive either a diet containing 40 g/day of the modified resistant starch or placebo (corn starch or regular flour) for 3 weeks on each diet, with a 3-week washout period between the two diets. BP is measured in the office, at home, and using a 24-h ambulatory device. Arterial stiffness is measured using carotid-to-femoral pulse wave velocity. Our primary endpoint is a reduction in ambulatory daytime systolic BP. Secondary endpoints include changes to circulating cytokines, immune markers, and modulation to the gut microbiome.Discussion: The findings of this study will provide the first evidence for the use of a combination of pre- and postbiotics to lower BP in humans. The results are expected at the end of 2021

Genes Influencing Circadian Differences in Blood Pressure in Hypertensive Mice

Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the ‘peak’ (n = 12) and ‘trough’ (n = 6) of diurnal BP. Using Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension