Impact of fibre supplementation on microbiome and resilience in healthy participants: A randomized, placebo-controlled clinical trial.

BACKGROUND AND AIMS: The gut microbiome exerts important roles in health, e.g., functions in metabolism and immunology. These functions are often exerted via short-chain fatty acid (SCFA) production by gut bacteria. Studies demonstrating causal relationships between interventions targeting the microbiome and clinical outcomes are limited. This study aimed to show a causal relationship between microbiome modulation through fibre intervention and health. METHODS AND RESULTS: This randomized, double-blind, cross-over study included 65 healthy subjects, aged 45-70 years, with increased metabolic risk (i.e., body mass index [BMI] 25-30 kg/m2, low to moderate daily dietary fibre intake, <30g/day). Subjects took daily a fibre mixture of Acacia gum and carrot powder or placebo for 12 weeks, with an 8-week wash-out period. Faecal samples for measurement of SCFAs and microbiome analysis were collected every 4 weeks. Before and after each intervention period subjects underwent the mixed-meal PhenFlex challenge Test (PFT). Health effects were expressed as resilience to the stressors of the PFT and as fasting metabolic and inflammatory state. The fibre mixture exerted microbiome modulation, with an increase in ß-diversity (p < 0.001). α-diversity was lower during fibre mixture intake compared to placebo after 4, 8 and 12 weeks (p = 0.002; p = 0.012; p = 0.031). There was no effect observed on faecal SCFA concentrations, nor on any of the primary clinical outcomes (Inflammatory resilience: p = 0.605, Metabolic resilience: p = 0.485). CONCLUSION: Although the intervention exerted effects on gut microbiome composition, no effects on SCFA production, on resilience or fasting metabolic and inflammatory state were observed in this cohort. REGISTRATION NUMBER CLINICALTRIALS.GOV: NCT04829396.

Design Issues in Personalized Nutrition Advice Systems.

The current health status of the general public can substantially benefit from a healthy diet. Using a personalized approach to initiate healthy dietary behavior seems to be a promising strategy, as individuals differ in terms of health status, subsequent dietary needs, and their desired behavior change support. However, providing personalized advice to a wide audience over a long period is very labor-intensive. This bottleneck can possibly be overcome by digitalizing the process of creating and providing personalized advice. An increasing number of personalized advice systems for different purposes is becoming available in the market, ranging from systems providing advice about just a single parameter to very complex systems that include many variables characterizing each individual situation. Scientific background is often lacking in these systems. In designing a personalized nutrition advice system, many design questions need to be answered, ranging from the required input parameters and accurate measurement methods (sense), type of modeling techniques to be used (reason), and modality in which the personalized advice is provided (act). We have addressed these topics in this viewpoint paper, and we have demonstrated the feasibility of setting up an infrastructure for providing personalized dietary advice based on the experience of 2 practical applications in a real-life setting.

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation.

Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.

Minor Changes in the Composition and Function of the Gut Microbiota During a 12-Week Whole Grain Wheat or Refined Wheat Intervention Correlate with Liver Fat in Overweight and Obese Adults.

BACKGROUND: Whole grain wheat (WGW) products are advocated as a healthy choice when compared with refined wheat (RW). One proposed mechanism for these health benefits is via the microbiota, because WGW contains multiple fibers. WGW consumption has been proposed to ameliorate nonalcoholic fatty liver disease, in which microbiota might play a role. OBJECTIVES: We investigated the effect of WGW compared with RW intervention on the fecal microbiota composition and functionality, and correlated intervention-induced changes in bacteria with changes in liver health parameters in adults with overweight or obesity. METHODS: We used data of a 12-wk double-blind, randomized, controlled, parallel trial to examine the effects of a WGW (98 g/d) or RW (98 g/d) intervention on the secondary outcomes fecal microbiota composition, predicted microbiota functionality, and stool consistency in 37 women and men (aged 45-70 y, BMI 25-35 kg/m2). The changes in microbiota composition, measured using 16S ribosomal RNA gene sequencing, after a 12-wk intervention were analyzed with nonparametric tests, and correlated with changes in liver fat and circulating concentrations of liver enzymes including alanine transaminase, aspartate transaminase, γ-glutamyltransferase, and serum amyloid A. RESULTS: The WGW intervention increased the mean (± SD) relative abundances of Ruminococcaceae_UCG-014 (baseline: 2.2 ± 4.6%, differential change over time (Δ) 0.51 ± 4.2%), Ruminiclostridium_9 (baseline: 0.065 ± 0.11%, Δ 0.054 ± 0.14%), and Ruminococcaceae_NK4A214_group (baseline: 0.37 ± 0.56%, Δ 0.17 ± 0.83%), and also the predicted pathway acetyl-CoA fermentation to butyrate II (baseline: 0.23 ± 0.062%, Δ 0.035 ± 0.059%), compared with the RW intervention (P values <0.05). A change in Ruminococcaceae_NK4A214_group was positively correlated with the change in liver fat, in both the WGW (ρ = 0.54; P = 0.026) and RW (ρ = 0.67; P = 0.024) groups. CONCLUSIONS: In middle-aged overweight and obese adults, a 12-wk WGW intervention increased the relative abundance of a number of bacterial taxa from the family Ruminococcaceae and increased predicted fermentation pathways when compared with an RW intervention. Potential protective health effects of replacement of RW by WGW on metabolic organs, such as the liver, via modulation of the microbiota, deserve further investigation.This trial was registered at clinicaltrials.gov as NCT02385149.

JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction.

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2-/- bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo.NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin's vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.

Whole Grain Wheat Consumption Affects Postprandial Inflammatory Response in a Randomized Controlled Trial in Overweight and Obese Adults with Mild Hypercholesterolemia in the Graandioos Study.

BACKGROUND: Whole grain wheat (WGW) consumption is associated with health benefits in observational studies. However, WGW randomized controlled trial (RCT) studies show mixed effects. OBJECTIVES: The health impact of WGW consumption was investigated by quantification of the body's resilience, which was defined as the "ability to adapt to a standardized challenge." METHODS: A double-blind RCT was performed with overweight and obese (BMI: 25-35 kg/m2) men (n = 19) and postmenopausal women (n = 31) aged 45-70 y, with mildly elevated plasma total cholesterol (>5 mmol/L), who were randomly assigned to either 12-wk WGW (98 g/d) or refined wheat (RW). Before and after the intervention a standardized mixed-meal challenge was performed. Plasma samples were taken after overnight fasting and postprandially (30, 60, 120, and 240 min). Thirty-one biomarkers were quantified focusing on metabolism, liver, cardiovascular health, and inflammation. Linear mixed-models evaluated fasting compared with postprandial intervention effects. Health space models were used to evaluate intervention effects as composite markers representing resilience of inflammation, liver, and metabolism. RESULTS: Postprandial biomarker changes related to liver showed decreased alanine aminotransferase by WGW (P = 0.03) and increased ß-hydroxybutyrate (P = 0.001) response in RW. Postprandial changes related to inflammation showed increased C-reactive protein (P = 0.001), IL-6 (P = 0.02), IL-8 (P = 0.007), and decreased IL-1B (P = 0.0002) in RW and decreased C-reactive protein (P < 0.0001), serum amyloid A (P < 0.0001), IL-8 (P = 0.02), and IL-10 (P < 0.0001) in WGW. Health space visualization demonstrated diminished inflammatory (P < 0.01) and liver resilience (P < 0.01) by RW, whereas liver resilience was rejuvenated by WGW (P < 0.05). CONCLUSIONS: Twelve-week 98 g/d WGW consumption can promote liver and inflammatory resilience in overweight and obese subjects with mildly elevated plasma cholesterol. The health space approach appeared appropriate to evaluate intervention effects as composite markers. This trial was registered at www.clinicaltrials.gov as NCT02385149.

Effects of dietary history on energy metabolism and physiological parameters in C57BL/6J mice.

Understanding body weight regulation is essential to fight obesity. Mouse studies, using different types of diets, showed conflicting results in terms of body weight persistence after changing from an ad libitum high-fat diet to an ad libitum low-fat diet. In this study, we questioned specifically whether the energy content of the diet has a lasting effect on energy balance and body weight, using multiple switches and two purified diets with a different fat-to-sugar ratio, but otherwise identical ingredients. Young-adult obesity-prone male C57BL/6J mice were fed single or double switches of semi-purified diets with either 10 energy % (en%) fat (LF) or 40en% fat (HF), with starch replaced by fat, while protein content remained equal. After none, one or two dietary changes, energy metabolism was assessed at 5, 14 and 19 weeks. We observed no systematic continuous compensation in diet and energy intake when returning to LF after HF consumption. Body weight, white adipose tissue mass and histology, serum metabolic parameters, energy expenditure and substrate usage all significantly reflected the current diet intake, independent of dietary changes. This contrasts with studies that used diets with different ingredients and showed persistent effects of dietary history on body weight, suggesting diet-dependent metabolic set points. We conclude that body weight and metabolic parameters 'settle', based on current energetic input and output. This study also highlights the importance of considering the choice of diet in physiological and metabolic intervention studies.

Individual and Group-Based Effects of In Vitro Fiber Interventions on the Fecal Microbiota.

The development of microbiome-targeted strategies is limited by individual differences in gut microbiome composition and metabolic responses to interventions. In vitro models that can replicate this variation allow us to conduct pre-clinical studies and assess efficacy. This study describes the exposure of 16 individual fecal microbiota samples to 5 different fibers using an in vitro system for the anaerobic cultivation of bacteria. The individual microbiota differed in composition and metabolite profiles (short-chain fatty acids and branched-chain fatty acids) after incubation with the fibers. Furthermore, microbiota composition after fiber incubation was significantly different between subjects with good intestinal health and subjects with Inflammatory Bowel Disease (IBD). α-diversity was differently affected by dietary fibers; for example, exposure to psyllium resulted in increased diversity in the healthy group and in decreased diversity in the IBD group. Instead, the functional metabolic profile did not differ between the two groups. Finally, the combination of all fibers, tested on the microbiota from IBD subjects, resulted in stronger overall effects on both microbiota composition and metabolite production compared to the single fibers. These results confirm that incubation with dietary fiber results in different compositional and functional effects on individual microbiota and that in vitro models represent successful tools for studying individual fiber effects.

Exploring the Potential of Personalized Dietary Advice for Health Improvement in Motivated Individuals With Premetabolic Syndrome: Pretest-Posttest Study.

BACKGROUND: Dietary quality plays an essential role in the prevention and management of metabolic syndrome (MetS). OBJECTIVE: The aim of this pilot study is to organize personalized dietary advice in a real-life setting and to explore the effects on dietary intake, metabolic health, and perceived health. METHODS: We followed a one-group pretest-posttest design and included 37 individuals at risk of MetS, who indicated motivation to change dietary behavior. For a period of 16 weeks, participants received personalized advice (t=0 and t=8) and feedback (t=0, t=4, t=8, t=12 and t=16) on dietary quality and metabolic health (ie, waist circumference, BMI, blood pressure, lipid profile, fasting glucose levels, and C-peptide). Personalized advice was generated in a two-stage process. In stage 1, an automated algorithm generated advice per food group, integrating data on individual dietary quality (Dutch Healthy Diet Index; total score 8-80) and metabolic health parameters. Stage 2 included a telephone consultation with a trained dietitian to define a personal dietary behavior change strategy and to discuss individual preferences. Dietary quality and metabolic health markers were assessed at t=0, t=8, and t=16. Self-perceived health was evaluated on 7-point Likert scales at t=0 and t=16. RESULTS: At the end of the study period, dietary quality was significantly improved compared with the baseline (Dutch Healthy Diet Index +4.3; P<.001). In addition, lipid profile (triglycerides, P=.02; total cholesterol, P=.01; high-density lipoprotein, P<.001; and low-density lipoprotein, P<.001), BMI (P<.001), waist circumference (P=.01), and C-peptide (P=.01) were all significantly improved, whereas plasma glucose increased by 0.23 nmol/L (P=.04). In line with these results, self-perceived health scores were higher at t=16 weeks than at baseline (+0.67; P=.005). CONCLUSIONS: This exploratory study showed that personalized dietary advice resulted in positive effects on dietary behavior, metabolic health, and self-perceived health in motivated pre-MetS adults. The study was performed in a do-it-yourself setting, highlighting the potential of at-home health improvement through dietary changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04595669; https://clinicaltrials.gov/ct2/show/NCT04595669.

Evaluation of Food-Intake Behavior in a Healthy Population: Personalized vs. One-Size-Fits-All.

In public health initiatives, generic nutrition advice (GNA) from national guidelines has a limited effect on food-intake improvement. Personalized nutrition advice (PNA) may enable dietary behavior change. A monocentric, randomized, parallel, controlled clinical trial was performed in males (n = 55) and females (n = 100) aged 25 to 70 years. Participants were allocated to control, GNA or PNA groups. The PNA group consisted of automatically generated dietary advice based on personal metabolic health parameters, dietary intake, anthropometric and hemodynamic measures, gender and age. Participants who received PNA (n = 51) improved their nutritional intake status for fruits P (p < 0.0001), whole grains (p = 0.008), unsalted nuts (p < 0.0001), fish (p = 0.0003), sugar-sweetened beverages (p = 0.005), added salt (p = 0.003) and less unhealthy choices (p = 0.002), whereas no improvements were observed in the control and GNA group. PNA participants were encouraged to set a goal for one or multiple food categories. Goal-setting led to greater improvement of food categories within the PNA group including; unsalted nuts (p < 0.0001), fruits (p = 0.0001), whole grains (p = 0.005), fish (p = 0.0001), dairy (p = 0.007), vegetables (p = 0.01) and unhealthy choices (p = 0.02). In a healthy population, participants receiving PNA changed their food-intake behavior more favorably than participants receiving GNA or no advice. When personal goals were set, nutritional behavior was more prone to change.

Current and Future Nutritional Strategies to Modulate Inflammatory Dynamics in Metabolic Disorders.

Obesity, type 2 diabetes, and other metabolic disorders have a large impact on global health, especially in Western countries. An important hallmark of metabolic disorders is chronic low-grade inflammation. A key player in chronic low-grade inflammation is dysmetabolism, which is defined as the inability to keep homeostasis resulting in loss of lipid control, oxidative stress, inflammation, and insulin resistance. Although often not yet detectable in the circulation, chronic low-grade inflammation can be present in one or multiple organs. The response to a metabolic challenge containing lipids may magnify dysfunctionalities at the tissue level, causing an overflow of inflammatory markers into the circulation and hence allow detection of early low-grade inflammation. Here, we summarize the evidence of successful application of metabolic challenge tests in type 2 diabetes, metabolic syndrome, obesity, and unhealthy aging. We also review how metabolic challenge tests have been successfully applied to evaluate nutritional intervention effects, including an "anti-inflammatory" mixture, dark chocolate, whole grain wheat and overfeeding. Additionally, we elaborate on future strategies to (re)gain inflammatory flexibility. Through epigenetic and metabolic regulation, the inflammatory response may be trained by regular mild and metabolic triggers, which can be understood from the perspective of trained immunity, hormesis and pro-resolution. New strategies to optimize dynamics of inflammation may become available.

White Adipose Tissue Response of Obese Mice to Ambient Oxygen Restriction at Thermoneutrality: Response Markers Identified, but no WAT Inflammation.

Obesity is associated with white adipose tissue (WAT) hypoxia and inflammation. We aimed to test whether mild environmental oxygen restriction (OxR, 13% O2), imposing tissue hypoxia, triggers WAT inflammation in obese mice. Thirteen weeks diet-induced obese male adult C57BL/6JOlaHsd mice housed at thermoneutrality were exposed for five days to OxR versus normoxia. WAT and blood were isolated and used for analysis of metabolites and adipokines, WAT histology and macrophage staining, and WAT transcriptomics. OxR increased circulating levels of haemoglobin and haematocrit as well as hypoxia responsive transcripts in WAT and decreased blood glucose, indicating systemic and tissue hypoxia. WAT aconitase activity was inhibited. Macrophage infiltration as marker for WAT inflammation tended to be decreased, which was supported by down regulation of inflammatory genes S100a8, Ccl8, Clec9a, Saa3, Mgst2, and Saa1. Other down regulated processes include cytoskeleton remodelling and metabolism, while response to hypoxia appeared most prominently up regulated. The adipokines coiled-coil domain containing 3 (CCDC3) and adiponectin, as well as the putative WAT hormone cholecystokinin (CCK), were reduced by OxR on transcript (Cck, Ccdc3) and/or serum protein level (adiponectin, CCDC3). Conclusively, our data demonstrate that also in obese mice OxR does not trigger WAT inflammation. However, OxR does evoke a metabolic response in WAT, with CCDC3 and adiponectin as potential markers for systemic or WAT hypoxia.

A 12-wk whole-grain wheat intervention protects against hepatic fat: the Graandioos study, a randomized trial in overweight subjects.

Background: Whole-grain wheat (WGW) is described as nutritionally superior to refined wheat (RW) and thus advocated as the healthy choice, although evidence from intervention studies is often inconsistent. The liver, as the central organ in energy metabolism, might be an important target organ for WGW interventions. Objective: The aim of this study was to investigate the potential benefits of WGW consumption compared with RW consumption on liver health and associated parameters. Design: We performed a double-blind, parallel trial in which 50 overweight 45- to 70-y-old men and postmenopausal women were randomly allocated to a 12-wk intervention with either WGW (98 g/d) or RW (98 g/d) products. Before and after the intervention we assessed intrahepatic triglycerides (IHTGs) and fat distribution by proton magnetic resonance spectroscopy/magnetic resonance imaging, fecal microbiota composition, adipose tissue gene expression, and several fasting plasma parameters, as well as postprandial plasma lipids after a mixed meal. Results: Fasting plasma cholesterol, triglycerides, nonesterified fatty acids, and insulin were not affected by RW or WGW intervention. We observed a substantial increase of 49.1% in IHTGs in the RW when compared with the WGW group (P = 0.033). Baseline microbiota composition could not predict the increase in IHTGs after RW, but gut microbiota diversity decreased in the RW group when compared with the WGW group (P = 0.010). In the WGW group, we observed increased postprandial triglyceride levels compared with the RW group (P = 0.020). In addition, the WGW intervention resulted in a trend towards lower fasting levels of the liver acute-phase proteins serum amyloid A (P = 0.057) and C-reactive protein (P = 0.064) when compared to the RW intervention. Conclusions: A 12-wk RW intervention increases liver fat and might contribute to the development of nonalcoholic fatty liver disease, whereas a 12-wk 98-g/d WGW intervention prevents a substantial increase in liver fat. Our results show that incorporating feasible doses of WGW in the diet at the expense of RW maintains liver health. The study was registered at clinicaltrials.gov as NCT02385149.

The impact of micronutrient status on health: correlation network analysis to understand the role of micronutrients in metabolic-inflammatory processes regulating homeostasis and phenotypic flexibility.

BACKGROUND: Vitamins and carotenoids are key micronutrients facilitating the maintenance of health, as evidenced by the increased risk of disease with low intake. Optimal phenotypic flexibility, i.e., the ability to respond to a physiological challenge, is an essential indicator of health status. Therefore, health can be measured by applying a challenge test and monitoring the response of relevant phenotypic processes. In this study, we assessed the correlation of three fat-soluble vitamins, (i.e., vitamin A or retinol, vitamin D3, two homologues of vitamin E) and four carotenoids (i.e., α-carotene, ß-carotene, ß-cryptoxanthin, and lycopene), with characteristics of metabolic and inflammatory parameters at baseline and in response to a nutritional challenge test (NCT) in a group of 36 overweight and obese male subjects, using proteomics and metabolomics platforms. The phenotypic flexibility concept implies that health can be measured by the ability to adapt to a NCT, which may offer a more sensitive way to assess changes in health status of healthy subjects. RESULTS: Correlation analyses of results after overnight fasting revealed a rather evenly distributed network in a number of relatively strong correlations per micronutrient, with minor overlap between correlation profiles of each compound. Correlation analyses of challenge response profiles for metabolite and protein parameters with micronutrient status revealed a network that is more skewed towards α-carotene and γ-tocopherol suggesting a more prominent role for these micronutrients in the maintenance of phenotypic flexibility. Comparison of the networks revealed that there is merely overlap of two parameters (inositol and oleic acid (C18:1)) affirming that there is a specific biomarker response profile upon NCT. CONCLUSIONS: Our study shows that applying the challenge test concept is able to reveal previously unidentified correlations between specific micronutrients and health-related processes, with potential relevance for maintenance of health that were not observed by correlating homeostatic measurements. This approach will contribute to insights on the influence of micronutrients on health and help to create efficient micronutrient intervention programs.

Early differences in metabolic flexibility between obesity-resistant and obesity-prone mice.

Decreased metabolic flexibility, i.e. a compromised ability to adjust fuel oxidation to fuel availability supports development of adverse consequences of obesity. The aims of this study were (i) to learn whether obesity-resistant A/J and obesity-prone C57BL/6J mice differ in their metabolic flexibility right after weaning; and (ii) to characterize possible differences in control of glucose homeostasis in these animals using glucose tolerance tests (GTT). A/J and C57BL/6J mice of both genders were maintained at 20 °C and weaned to standard low-fat diet at 30 days of age. During the first day after weaning, using several separate animal cohorts, (i) GTT was performed using 1 or 3 mg glucose/g body weight (BW), while glucose was administered either orally (OGTT) or intraperitoneally (IPGTT) at 20 °C; and (ii) indirect calorimetry (INCA) was performed, either in a combination with oral gavage of 1 or 7.5 mg glucose/g BW, or during a fasting/re-feeding transition. INCA was conducted either at 20 °C or 34 °C. Results of both OGTT and IPGTT using 1 mg glucose/g BW at 20 °C, and INCA using 7.5 mg glucose/g BW at 34 °C, indicated higher glucose tolerance and higher metabolic flexibility to glucose, respectively, and lower fasting glycemia in A/J mice as compared with C57BL/6J mice. Thus, control of whole body glucose metabolism between A/J and C57BL/6J mice represents a phenotypic feature differentiating between the strains right after weaning.

Nutrigenomics of body weight regulation: a rationale for careful dissection of individual contributors.

Body weight stability may imply active regulation towards a certain physiological condition, a body weight setpoint. This interpretation is ill at odds with the world-wide increase in overweight and obesity. Until now, a body weight setpoint has remained elusive and the setpoint theory did not provide practical clues for body weight reduction interventions. For this an alternative theoretical model is necessary, which is available as the settling point model. The settling point model postulates that there is little active regulation towards a predefined body weight, but that body weight settles based on the resultant of a number of contributors, represented by the individual's genetic predisposition, in interaction with environmental and socioeconomic factors, such as diet and lifestyle. This review refines the settling point model and argues that by taking body weight regulation from a settling point perspective, the road will be opened to careful dissection of the various contributors to establishment of body weight and its regulation. This is both necessary and useful. Nutrigenomic technologies may help to delineate contributors to body weight settling. Understanding how and to which extent the different contributors influence body weight will allow the design of weight loss and weight maintenance interventions, which hopefully are more successful than those that are currently available.

Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet.

Restriction of a high-fat diet (HFD) and a change to a low-fat diet (LFD) are two interventions that were shown to promote weight loss and improve parameters of metabolic health in obesity. Examination of the biochemical and molecular responses of white adipose tissue (WAT) to these interventions has not been performed so far. Here, male C57BL/6JOlaHsd mice, harboring an intact nicotinamide nucleotide transhydrogenase gene, were fed a purified 40 energy% HFD for 14 weeks to induce obesity. Afterward, mice were divided into three dietary groups: HFD (maintained on HFD), LFD (changed to LFD with identical ingredients), and HFD-CR (restricted to 70 % of the HFD). The effects of the interventions were examined after 5 weeks. Beneficial effects were seen for both HFD-CR and LFD (compared to HFD) regarding physiological parameters (body weight and fat mass) and metabolic parameters, including circulating insulin and leptin levels. Macrophage infiltration in WAT was reduced by both interventions, although more effectively by HFD-CR. Strikingly, molecular parameters in WAT differed between HFD-CR and LFD, with increased activation of mitochondrial carbohydrate and fat metabolism in HFD-CR mice. Our results confirm that restriction of the amount of dietary intake and reduction in the dietary energy content are both effective in inducing weight loss. The larger decrease in WAT inflammation and increase in mitochondrial carbohydrate metabolism may be due to a larger degree of energy restriction in HFD-CR, but could also be due to superior effectiveness of dietary restriction in weight loss strategies.

Thermoneutrality results in prominent diet-induced body weight differences in C57BL/6J mice, not paralleled by diet-induced metabolic differences.

SCOPE: Mice are usually housed at 20-24 °C. At thermoneutrality (28 °C) larger diet-induced differences in obesity are seen. We tested whether this leads to large differences in metabolic health parameters. METHODS AND RESULTS: We performed a 14-wk dietary intervention in C57BL/6J mice at 28 °C and assessed adiposity and metabolic health parameters for a semipurified low fat (10 energy%) diet and a moderate high fat (30 energy%) diet. A large and significant diet-induced differential increase in body weight, adipose tissue mass, adipocyte size, serum leptin level, and, to some extent, cholesterol level was observed. No adipose tissue inflammation was seen. No differential effect of the diets on serum glucose, free fatty acids, triacylglycerides, insulin, adiponectin, resistin, PAI-1, MMP-9, sVCAM-1, sICAM-1, sE-selectin, IL-6, ApoE, fibrinogen levels, or HOMA index was observed. Also in muscle no differential effect on mitochondrial density, mitochondrial respiratory control ratio, or mRNA expression of metabolic genes was found. Finally, in liver no differential effect on weight, triacylglycerides level, aconitase/citrate synthase activity ratio was seen. CONCLUSION: Low fat diet and moderate high fat diet induce prominent body weight differences at thermoneutrality, which is not paralleled by metabolic differences. Our data rather suggest that thermoneutrality alters metabolic homeostasis.

BIOCLAIMS standard diet (BIOsd): a reference diet for nutritional physiology.

Experimental replication is fundamental for practicing science. To reduce variability, it is essential to control sources of variation as much as possible. Diet is an important factor that can influence many processes and functional outcomes in studies performed with rodent models. This is especially true for, but not limited to, nutritional studies. To compare functional effects of different nutrients, it is important to use standardized, semi-purified diets. Here, we propose and describe a standard reference diet, the BIOCLAIMS standard diet. The diet is AIN-93 based, but further defined with dietary and experimental requirements taken into account that allow for experiments with bioactive food components and natural (non-expensive) labeling. This diet will be implemented by two European research consortia, Mitofood and BIOCLAIMS, to ensure inter-laboratory comparability.