A systematic review of associations between day-to-day variability in meal pattern and body weight, components of the metabolic syndrome and cognitive function.

BACKGROUND: Meal pattern is a potential health determinant. Previously, mean values for properties of meal pattern, such as daily meal frequency, have been considered. Means, however, obscure variability between-day (irregular or chaotic eating). This systematic review aimed to identify and critique published methods used to characterise between-day variability in meal pattern, and to explore relationships between this and obesity, as well as associated health outcomes. METHODS: Using relevant databases, a systematic search was undertaken for studies with adults and children in which between-day variability in meal pattern was measured, and related to body weight, metabolic syndrome components and cognitive function. RESULTS: In 34 papers identified (28 observational and six intervention studies), between-day variability in meal pattern was characterised by a variety of methods. These ranged from single questions about intake regularity to more complex methods quantifying the degree of variability. Assumptions were made, such as there being three main meals, resulting in dissociation from the "clock time" of eating. In 24 of the papers, between-day variability in meal pattern was associated with negative weight and health outcomes including higher weight, reduced thermogenic response to meals and poorer academic achievement. CONCLUSIONS: Between-day variability in meal pattern is a promising research area that might inform low-cost public health interventions. However, current methods of characterising between-day variability tend to make assumptions and be inconsistent in the meal pattern properties considered. Well controlled dietary intervention studies are required to confirm causation.

A comparative, randomised MRI study of the physiological and appetitive responses to gelling (alginate) and non-gelling nasogastric tube feeds in healthy men.

Inclusion in nasogastric tube feeds (NGTF) of acid-sensitive, seaweed-derived alginate, expected to form a reversible gel in the stomach, may create a more normal intragastric state and modified gastrointestinal responses. This may ameliorate NGTF-associated risk of diarrhoea, upper gastrointestinal symptoms and appetite suppression. In a randomised, crossover, comparison study, undertaken in twelve healthy males, an alginate-containing feed (F + ALG) or one that was alginate-free (F-ALG) (300 ml) was given over 1 h with a 7-14-d washout period between treatments. Baseline and for 4-h post-feed initiation, MRI measurements were made to establish small bowel water content (SBWC), gastric contents volume (GCV) and appearance, and superior mesenteric artery blood flux. Blood glucose and gut peptides were measured. Subjective appetite and upper gastrointestinal symptoms scores were obtained. Ad libitum pasta consumption 3-h post-feeding was measured. F + ALG exhibited a gastric appearance consistent with gelling surrounded by a freely mobile water halo. Significant main effects of feed were seen for SBWC (P = 0·03) and peptide YY (PYY) (P = 0·004) which were attributed to generally higher values for SBWC with F + ALG (max difference between adjusted means 72 ml at 210 min) and generally lower values for PYY with F + ALG. GCV showed a faster reduction with F + ALG, less between-participant variation and a feed-by-time interaction (P = 0·04). Feed-by-time interactions were also seen with glucagon-like-peptide 1 (GLP-1) (P = 0·02) and glucose-dependent insulinotropic polypeptide (GIP) (P = 0·002), both showing a blunted response with F + ALG. Apparent intragastric gelling with F + ALG and subsequent differences in gastrointestinal and endocrine responses have been demonstrated between an alginate-containing and alginate-free feed.

Age- and sex-specific effects of a long-term lifestyle intervention on body weight and cardiometabolic health markers in adults with prediabetes: results from the diabetes prevention study PREVIEW.

AIMS/HYPOTHESIS: Lifestyle interventions are the first-line treatment option for body weight and cardiometabolic health management. However, whether age groups or women and men respond differently to lifestyle interventions is under debate. We aimed to examine age- and sex-specific effects of a low-energy diet (LED) followed by a long-term lifestyle intervention on body weight, body composition and cardiometabolic health markers in adults with prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). METHODS: This observational study used longitudinal data from 2223 overweight participants with prediabetes in the multicentre diabetes prevention study PREVIEW. The participants underwent a LED-induced rapid weight loss (WL) period followed by a 3 year lifestyle-based weight maintenance (WM) intervention. Changes in outcomes of interest in prespecified age (younger: 25-45 years; middle-aged: 46-54 years; older: 55-70 years) or sex (women and men) groups were compared. RESULTS: In total, 783 younger, 319 middle-aged and 1121 older adults and 1503 women and 720 men were included in the analysis. In the available case and complete case analyses, multivariable-adjusted linear mixed models showed that younger and older adults had similar weight loss after the LED, whereas older adults had greater sustained weight loss after the WM intervention (adjusted difference for older vs younger adults -1.25% [95% CI -1.92, -0.58], p<0.001). After the WM intervention, older adults lost more fat-free mass and bone mass and had smaller improvements in 2 h plasma glucose (adjusted difference for older vs younger adults 0.65 mmol/l [95% CI 0.50, 0.80], p<0.001) and systolic blood pressure (adjusted difference for older vs younger adults 2.57 mmHg [95% CI 1.37, 3.77], p<0.001) than younger adults. Older adults had smaller decreases in fasting and 2 h glucose, HbA1c and systolic blood pressure after the WM intervention than middle-aged adults. In the complete case analysis, the above-mentioned differences between middle-aged and older adults disappeared, but the direction of the effect size did not change. After the WL period, compared with men, women had less weight loss (adjusted difference for women vs men 1.78% [95% CI 1.12, 2.43], p<0.001) with greater fat-free mass and bone mass loss and smaller improvements in HbA1c, LDL-cholesterol and diastolic blood pressure. After the WM intervention, women had greater fat-free mass and bone mass loss and smaller improvements in HbA1c and LDL-cholesterol, while they had greater improvements in fasting glucose, triacylglycerol (adjusted difference for women vs men -0.08 mmol/l [-0.11, -0.04], p<0.001) and HDL-cholesterol. CONCLUSIONS/INTERPRETATION: Older adults benefited less from a lifestyle intervention in relation to body composition and cardiometabolic health markers than younger adults, despite greater sustained weight loss. Women benefited less from a LED followed by a lifestyle intervention in relation to body weight and body composition than men. Future interventions targeting older adults or women should take prevention of fat-free mass and bone mass loss into consideration. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01777893.

Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging.

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.

The PREVIEW intervention study: Results from a 3-year randomized 2 x 2 factorial multinational trial investigating the role of protein, glycaemic index and physical activity for prevention of type 2 diabetes.

AIM: To compare the impact of two long-term weight-maintenance diets, a high protein (HP) and low glycaemic index (GI) diet versus a moderate protein (MP) and moderate GI diet, combined with either high intensity (HI) or moderate intensity physical activity (PA), on the incidence of type 2 diabetes (T2D) after rapid weight loss. MATERIALS AND METHODS: A 3-year multicentre randomized trial in eight countries using a 2 x 2 diet-by-PA factorial design was conducted. Eight-week weight reduction was followed by a 3-year randomized weight-maintenance phase. In total, 2326 adults (age 25-70 years, body mass index ≥ 25 kg/m2 ) with prediabetes were enrolled. The primary endpoint was 3-year incidence of T2D analysed by diet treatment. Secondary outcomes included glucose, insulin, HbA1c and body weight. RESULTS: The total number of T2D cases was 62 and the cumulative incidence rate was 3.1%, with no significant differences between the two diets, PA or their combination. T2D incidence was similar across intervention centres, irrespective of attrition. Significantly fewer participants achieved normoglycaemia in the HP compared with the MP group (P < .0001). At 3 years, normoglycaemia was lowest in HP-HI (11.9%) compared with the other three groups (20.0%-21.0%, P < .05). There were no group differences in body weight change (-11% after 8-week weight reduction; -5% after 3-year weight maintenance) or in other secondary outcomes. CONCLUSIONS: Three-year incidence of T2D was much lower than predicted and did not differ between diets, PA or their combination. Maintaining the target intakes of protein and GI over 3 years was difficult, but the overall protocol combining weight loss, healthy eating and PA was successful in markedly reducing the risk of T2D. This is an important clinically relevant outcome.

Effects of consuming later evening meal v. earlier evening meal on weight loss during a weight loss diet: a randomised clinical trial.

Previous evidence confirms a relationship between the timing of food intake and weight loss. We aimed to evaluate the effect of late v. early evening meal (EEM) consumption on weight loss and cardiometabolic risk factors in women during a weight loss programme. Eighty-two healthy women (BMI 27-35 kg/m2; age 18-45 years) were randomly assigned to two groups: EEM group (eating at 19.00-19.30 hours) or late evening meal (LEM) group (eating at 22.30-23.00 hours), for 12 weeks. Compared with the LEM group, the EEM group had a greater mean reduction in weight (EEM: -6·74 (sd 1·92) kg; LEM: -4·81 (sd 2·22) kg; P < 0·001), BMI (EEM: -2·60 (sd 0·71) kg/m2; LEM: -1·87 (sd 0·85) kg/m2; P < 0·001), waist circumference (EEM: -8 (sd 3·25) cm; LEM: -6 (sd 3·05) cm, P = 0·007), total cholesterol (EEM: -0·51 (sd 0·19) mmol/l, LEM: -0·43 (sd 0·19) mmol/l, P = 0·038), TAG (EEM: -0·28 (sd 0·10) mmol/l, LEM: -0·19 (sd 0·10) mmol/l, P < 0·001) and homoeostasis model assessment of insulin resistance (EEM: -0·83 (sd 0·37); LEM: -0·55 (sd 0·28), P < 0·001) after 12 weeks. In conclusion, eating an earlier evening meal resulted in favourable changes in weight loss and plasma cardiometabolic risk markers during a weight loss programme.

Influence of cardiac autonomic neuropathy on cardiac repolarisation during incremental adrenaline infusion in type 1 diabetes.

AIMS/HYPOTHESIS: We examined the effect of a standardised sympathetic stimulus, incremental adrenaline (epinephrine) infusion on cardiac repolarisation in individuals with type 1 diabetes with normal autonomic function, subclinical autonomic neuropathy and established autonomic neuropathy. METHODS: Ten individuals with normal autonomic function and baroreceptor sensitivity tests (NAF), seven with subclinical autonomic neuropathy (SAN; normal standard autonomic function tests and abnormal baroreceptor sensitivity tests); and five with established cardiac autonomic neuropathy (CAN; abnormal standard autonomic function and baroreceptor tests) underwent an incremental adrenaline infusion. Saline (0.9% NaCl) was infused for the first hour followed by 0.01 µg kg-1 min-1 and 0.03 µg kg-1 min-1 adrenaline for the second and third hours, respectively, and 0.06 µg kg-1 min-1 for the final 30 min. High resolution ECG monitoring for QTc duration, ventricular repolarisation parameters (T wave amplitude, T wave area symmetry ratio) and blood sampling for potassium and catecholamines was performed every 30 min. RESULTS: Baseline heart rate was 68 (95% CI 60, 76) bpm for the NAF group, 73 (59, 87) bpm for the SAN group and 84 (78, 91) bpm for the CAN group. During adrenaline infusion the heart rate increased differently across the groups (p = 0.01). The maximum increase from baseline (95% CI) in the CAN group was 22 (13, 32) bpm compared with 11 (7, 15) bpm in the NAF and 10 (3, 18) bpm in the SAN groups. Baseline QTc was 382 (95% CI 374, 390) ms in the NAF, 378 (363, 393) ms in the SAN and 392 (367, 417) ms in the CAN groups (p = 0.31). QTc in all groups lengthened comparably with adrenaline infusion. The longest QTc was 444 (422, 463) ms (NAF), 422 (402, 437) ms (SAN) and 470 (402, 519) ms (CAN) (p = 0.09). T wave amplitude and T wave symmetry ratio decreased and the maximum decrease occurred earlier, at lower infused adrenaline concentrations in the CAN group compared with NAF and SAN groups. AUC for the symmetry ratio was different across the groups and was lowest in the CAN group (p = 0.04). Plasma adrenaline rose and potassium fell comparably in all groups. CONCLUSIONS/INTERPRETATION: Participants with CAN showed abnormal repolarisation in some measures at lower adrenaline concentrations. This may be due to denervation adrenergic hypersensitivity. Such individuals may be at greater risk of cardiac arrhythmias in response to physiological sympathoadrenal challenges such as stress or hypoglycaemia.

The effects of moderate alterations in adrenergic activity on acute appetite regulation in obese women: A randomised crossover trial.

BACKGROUND: Previous evidence has demonstrated that serum leptin is correlated with appetite in combination with, but not without, modest exercise. AIM: The present experiments investigated the effects of exogenous adrenaline and α/ß adrenoceptor blockade in combination with moderate exercise on serum leptin concentrations, appetite/satiety sensations and subsequent food intake in obese women. METHODS: A total of 10 obese women ((mean ± SEM), age: 50 (1.9) years, body mass index 36 (4.1) kg/m2, waist 104.8 (4.1) cm) participated in two separate, double-blind randomised experimental trials. Experiment 1: moderate exercise after α/ß adrenergic blocker (labetalol, 100 mg orally) versus moderate exercise plus placebo; experiment 2: adrenaline infusion for 20 minutes versus saline infusion. Appetite/satiety and biochemistry were measured at baseline, pre- and immediately post-intervention, then 1 hour post-intervention (i.e., before dinner). Food intake was assessed via ad libitum buffet-style dinner. RESULTS: No differences were found in appetite/satiety, subsequent food intake or serum leptin in any of the studies (experiment 1 or experiment 2). In experiment 1, blood glucose was higher (p < 0.01) and plasma free fatty acids lower (p = 0.04) versus placebo. In experiment 2, plasma free fatty acids (p < 0.05) increased after adrenaline versus saline infusion. CONCLUSIONS: Neither inhibition of exercise-induced adrenergic activity by combined α/ß adrenergic blockade nor moderate increases in adrenergic activity induced by intravenous adrenaline infusion affected acute appetite regulation.

Glycaemic, gastrointestinal, hormonal and appetitive responses to pearl millet or oats porridge breakfasts: a randomised, crossover trial in healthy humans.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

Vitamin intake is associated with improved visuospatial and verbal semantic memory in middle-aged individuals.

OBJECTIVES: Factors maintaining cognitive health are still largely unknown. In particular, the cognitive benefits associated with vitamin intake and vitamin supplementation are disputed. We investigated self-reported vitamin intake and serum vitamin levels with performance in cognitive factors sensitive to dementia progression in two large middle-aged general population cohorts. METHODS: Survey data were used to assess regular vitamin intake in 4400 NCDS 1958 and 1177 TwinsUK cohort members, and serum homocysteine and B vitamin levels were measured in 675 individuals from the TwinsUK study. Principal component analysis was applied to cognitive test performance from both cohorts resulting in two dementia-sensitive cognitive factors reflecting visuospatial associative memory and verbal semantic memory. RESULTS: In both cohorts, individuals who reported regular intake of vitamins, particularly B vitamins, showed significantly better performance in visuospatial associative memory and verbal semantic memory (P < 0.001). A significant association was also found between homocysteine levels, vitamin serum concentration and visuospatial associative memory performance which indicated that individuals with high B vitamin and homocysteine levels showed better visuospatial associative memory performance than individuals with low vitamin B levels (P < 0.05). DISCUSSION: The findings demonstrate that early dementia-sensitive cognitive changes can be identified in middle-aged asymptomatic individuals and that regular vitamin intake is associated with improved cognitive performance. These findings reinforce the potential cognitive benefits of regular vitamin intake, which should be considered as an economically viable therapeutic strategy for maintaining cognitive health.

A workshop on 'Dietary Sweetness-Is It an Issue?'

This report summarises a workshop convened by ILSI Europe on 3 and 4 April 2017 to discuss the issue of dietary sweetness. The objectives were to understand the roles of sweetness in the diet, establish whether exposure to sweetness affects diet quality and energy intake, and consider whether sweetness per se affects health. Although there may be evidence for tracking of intake of some sweet components of the diet through childhood, evidence for tracking of whole diet sweetness, or through other stages of maturity are lacking. The evidence to date does not support adverse effects of sweetness on diet quality or energy intake, except where sweet food choices increase intake of free sugars. There is some evidence for improvements in diet quality and reduced energy intake where sweetness without calories replaces sweetness with calories. There is a need to understand the physiological and metabolic relevance of sweet taste receptors on the tongue, in the gut and elsewhere in the body, as well as possible differentiation in the effects of sustained consumption of individual sweeteners. Despite a plethora of studies, there is no consistent evidence for an association of sweetness sensitivity/preference with obesity or type 2 diabetes. A multifaceted integrated approach, characterising nutritive and sensory aspects of the whole diet or dietary patterns, may be more valuable in providing contextual insight. The outcomes of the workshop could be used as a scientific basis to inform the expert community and create more useful dialogue among health care professionals.

Effects of sprint interval training on ectopic lipids and tissue-specific insulin sensitivity in men with non-alcoholic fatty liver disease.

PURPOSE: This study examined the feasibility of sprint interval exercise training (SIT) for men with non-alcoholic fatty liver disease (NAFLD) and its effects on intrahepatic triglyceride (IHTG), insulin sensitivity (hepatic and peripheral), visceral (VAT) and subcutaneous adipose tissue (ScAT). METHODS: Nine men with NAFLD (age 41 ± 8 years; BMI 31.7 ± 3.1 kg m-2; IHTG 15.6 ± 8.3%) were assessed at: (1) baseline (2) after a control phase of no intervention (pre-training) and (3) after 6 weeks of SIT (4-6 maximal 30 s cycling intervals, three times per week). IHTG, VAT and ScAT were measured using magnetic resonance spectroscopy or imaging and insulin sensitivity was assessed via dual-step hyperinsulinaemic-euglycaemic clamp with [6,6-D2] glucose tracer. RESULTS: Participants adhered to SIT, completing ≥ 96.7% of prescribed intervals. SIT increased peak oxygen uptake [[Formula: see text] peak: + 13.6% (95% CI 8.8-18.2%)] and elicited a relative reduction in IHTG [- 12.4% (- 31.6 to 6.7%)] and VAT [- 16.9% (- 24.4 to - 9.4%); n = 8], with no change in body weight or ScAT. Peripheral insulin sensitivity increased throughout the study (n = 8; significant main effect of phase) but changes from pre- to post-training were highly variable (range - 18.5 to + 58.7%) and not significant (P = 0.09), despite a moderate effect size (g* = 0.63). Hepatic insulin sensitivity was not influenced by SIT. CONCLUSIONS: SIT is feasible for men with NAFLD in a controlled laboratory setting and is able to reduce IHTG and VAT in the absence of weight loss.

Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: Results of a randomized controlled trial using 2 dietary approaches.

Short-term very-low-energy diets (VLEDs) are used in clinical practice prior to bariatric surgery, but regimens vary and outcomes of a short intervention are unclear. We examined the effect of 2 VLEDs, a food-based diet (FD) and a meal-replacement plan (MRP; LighterLife UK Limited, Harlow, UK), over the course of 2 weeks in a randomized controlled trial. We collected clinical and anthropometric data, fasting blood samples, and dietary evaluation questionnaires. Surgeons took liver biopsies and made a visual assessment of the liver. We enrolled 60 participants of whom 54 completed the study (FD, n = 26; MRP, n = 28). Baseline demographic features, reported energy intake, dietary evaluation and liver histology were similar in the 2 groups. Both diets induced significant weight loss. Perceived difficulty of surgery correlated significantly with the degree of steatosis on histology. There were reductions in the circulating inflammatory mediators C-reactive protein, fetuin-A and interleukin-6 between baseline (pre-diet) and post-diet. The diets achieved similar weight loss and reduction in inflammatory biomarkers. There were no significant differences in perceived operative difficulty or between patients' evaluation of diet satisfaction, ease of use or hunger frequency. Non-alcoholic fatty liver disease histology assessments post-diet were also not significantly different between diets. The results of this study show the effectiveness of short-term VLEDs and energy restriction, irrespective of macronutrient composition, although the small sample size precluded detection of subtle differences between interventions.

Beneficial effects of replacing diet beverages with water on type 2 diabetic obese women following a hypo-energetic diet: A randomized, 24-week clinical trial.

AIMS: To compare the effect of replacing diet beverages (DBs) with water or continuing to drink DBs in patients with type 2 diabetes during a 24-week weight loss program. The primary endpoint was the effect of intervention on weight over a 24-week period. The main secondary endpoints included anthropometric measurement and glucose and fat metabolism during the 24-week period. METHODS: A total of 81 overweight and obese women with type 2 diabetes, who usually consumed DBs in their diet, were asked to either substitute water for DBs or continue drinking DBs five times per week after lunch for 24 weeks (DBs group) during a weight loss program. RESULTS: Compared with the DBs group, the water group had a greater decrease in weight (water, -6.40 ± 2.42 kg; DBs, -5.25 ± 1.60 kg; P = .006), in BMI (water, -2.49 ± 0.92 kg/m2 ; DBs, -2.06 ± 0.62 kg/m2 ; P = .006), in FPG (water, -1.63 ± 0.54 mmol/L; DBs, -1.29 ± 0.48 mmol/L, P = .005), in fasting insulin (water, -5.71 ± 2.30 m lU/mL; DBs, -4.16 ± 1.74 m lU/mL, P = .011), in HOMA IR (water, -3.20 ± 1.17; DBs, -2.48 ± 0.99, P = 003) and in 2 hour postprandial glucose (water, -1.67 ± 0.62 mmol/L; DBs, -1.35 ± 0.39 mmol/L; P = 0.027) over the 24-week period. However, there was no significant time × group interaction for waist circumference, lipid profiles and HbA1c within both groups over the 24-week period. CONCLUSION: Replacement of DBs with water after the main meal in obese adult women with type 2 diabetes may lead to more weight reduction during a weight loss program.

Report and Application of a Tool Compound Data Set.

Small molecule tool compounds have enabled profound advances in life science research. These chemicals are potent, cell active, and selective, and, thus, are suitable for interrogating biological processes. For these chemicals to be useful they must be correctly characterized and researchers must be aware of them. We mined the ChEMBL bioactivity database to identify high quality tool compounds in an unbiased way. We identified 407 best-in-class compounds for 278 protein targets, and these are reported in an annotated data set. Additionally, we developed informatics functions and a web application for data visualization and automated pharmacological hypothesis generation. These functions were used to predict inhibitors of the Chromobox Protein Homologue 5 (CBX5) mediated gene repression pathway that currently lacks appropriate inhibitors. The predictions were subsequently validated by a highly specific cell based assay, revealing new chemical modulators of CBX5-mediated heterochromatin formation. This data set and associated functions will help researchers make the best use of these valuable compounds.

Effects of Bolus and Continuous Nasogastric Feeding on Gastric Emptying, Small Bowel Water Content, Superior Mesenteric Artery Blood Flow, and Plasma Hormone Concentrations in Healthy Adults: A Randomized Crossover Study.

OBJECTIVE: We aimed to demonstrate the effect of continuous or bolus nasogastric feeding on gastric emptying, small bowel water content, and splanchnic blood flow measured by magnetic resonance imaging (MRI) in the context of changes in plasma gastrointestinal hormone secretion. BACKGROUND: Nasogastric/nasoenteral tube feeding is often complicated by diarrhea but the contribution of feeding strategy to the etiology is unclear. METHODS: Twelve healthy adult male participants who underwent nasogastric intubation before a baseline MRI scan, received 400  mL of Resource Energy (Nestle) as a bolus over 5 minutes or continuously over 4  hours via pump in this randomized crossover study. Changes in gastric volume, small bowel water content, and superior mesenteric artery blood flow and velocity were measured over 4  hours using MRI and blood glucose and plasma concentrations of insulin, peptide YY, and ghrelin were assayed every 30 minutes. RESULTS: Bolus nasogastric feeding led to significant elevations in gastric volume (P < 0.0001), superior mesenteric artery blood flow (P < 0.0001), and velocity (P = 0.0011) compared with continuous feeding. Both types of feeding reduced small bowel water content, although there was an increase in small bowel water content with bolus feeding after 90 minutes (P < 0.0068). Similarly, both types of feeding led to a fall in plasma ghrelin concentration although this fall was greater with bolus feeding (P < 0.0001). Bolus feeding also led to an increase in concentrations of insulin (P = 0.0024) and peptide YY (P < 0.0001), not seen with continuous feeding. CONCLUSION: Continuous nasogastric feeding does not increase small bowel water content, thus fluid flux within the small bowel is not a major contributor to the etiology of tube feeding-related diarrhea.

The Effects of Insulin Resistance on Individual Tissues: An Application of a Mathematical Model of Metabolism in Humans.

Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper, we use a previously derived system of 12 first-order coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin-resistant tissue. Second, insulin resistance causes a fatty liver, and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is seen.

Effects of prolonged hypoxia and bed rest on appetite and appetite-related hormones.

Environmental hypoxia and inactivity have both been shown to modulate appetite. To elucidate the independent and combined effects of hypoxia and bed rest-induced inactivity on appetite-related hormones and subjective appetite, eleven healthy, non-obese males underwent three experimental interventions in a cross-over and randomized fashion: 1) Hypoxic confinement combined with daily moderate-intensity exercise (HAMB, FiO2 = 0.141 ± 0.004; PiO2 = 90.0 ± 0.4 mmHg) 2) Bed rest in normoxia (NBR, FiO2 = 0.209; PiO2 = 133.1 ± 0.3 mmHg) and 3) Bed rest in hypoxia (HBR, FiO2 = 0.141 ± 0.004; PiO2 = 90.0 ± 0.4 mmHg). A mixed-meal tolerance test (MTT), followed by an ad libitum meal were performed before (Pre) and after 16-days (Post) of each intervention. Composite satiety scores (CSS) during the MTT were calculated from visual analogue scores, while fasting and postprandial concentrations of total ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and leptin were quantified from arterialized-venous samples. Postprandial CSS were significantly lower at Post compared to Pre in NBR only (P < 0.05) with no differences observed in ad libitum meal intakes. Postprandial concentrations and incremental area under the curve (AUC) for total ghrelin and PYY were unchanged following all interventions. Postprandial GLP-1 concentrations were only reduced at Post following HBR (P < 0.05) with resulting AUC changes being significantly lower compared to HAMB (P < 0.01). Fasting leptin was reduced following HAMB (P < 0.05) with no changes observed following NBR and HBR. These findings suggest that independently, 16-day of simulated altitude exposure (∼4000 m) and bed rest-induced inactivity do not significantly alter subjective appetite or ad libitum intakes. The measured appetite-related hormones following both HAMB and HBR point to a situation of hypoxia-induced appetite stimulation, although this did not reflect in higher ad libitum intakes. CLINICAL TRIAL REGISTRATION NUMBER: NCT02293772.

Epigenetic roots of immunologic disease and new methods for examining chromatin regulatory pathways.

The ability to accurately quantitate and experimentally examine epigenetic modifications across the human genome has exploded in the past decade. This has given rise to a wealth of new information concerning the contributions of epigenetic regulatory networks to the pathogenesis of human disease. In particular, immunological disorders have strong developmental roots in chromatin regulatory pathways. In this review, we focus on the epigenetic signatures and new discoveries revealing the epigenetic compositions of specific immunological cancers and autoimmune diseases. We also comment on the conserved epigenetic roots among diverse immunological disorders and suggest inhibition strategies that may be relevant for future treatment. Finally, we highlight emerging experimental tools with the capability to examine the mechanisms of chromatin regulatory enzymes with a high level of temporal control. The knowledge of genetic and epigenetic defects in immunological disease combined with new experimental approaches will elucidate the contribution of individual enzymes in complex epigenetic regulatory networks. This could lead to new diagnostic and therapeutic approaches for some very diverse and difficult to treat human diseases.