[This corrects the article DOI: 10.1371/journal.pone.0282816.].

Dietary restriction (DR) improves insulin sensitivity, however, it has not been tested in long-term interventions and with diet type as variable. Therefore, we exposed mice to either a low-fat (LF) or high-fat-sucrose (HFS) diet, either fed ad libitum (AL) or in a DR regimen from weaning till 2 years of age. Using an oral glucose tolerance test with [6,6-2H2]-labelled glucose, we found that DR markedly reduced plasma insulin concentrations and strongly elevated hepatic and peripheral insulin sensitivity when compared to AL cohorts. These effects of DR, however, appeared to depend on diet and age, with stable increases in hepatic and peripheral insulin sensitivities across all ages in the LF condition, while these became clearly less elevated in the HFS condition with advancing age.

Background: Roux-en-Y gastric bypass (RYGB) surgery results in weight reduction and decreased energy intake and can ameliorate type 2 diabetes. These beneficial effects are usually attributed to changes in hunger and satiety and relatively rapid improvements in glycemic control, but these effects may depend on dietary adherence. The aim of this study is to investigate the relatively early effects of RYGB surgery on weight reduction (by focusing on eating patterns) and glycemic control in rats subjected to a healthy maintenance diet or an unhealthy Western-style diet. Methods: Rats were fed a high-fat diet with added sucrose (HF/S) or a low-fat (LF) diet. Body weight, high-resolution tracking of meal-related parameters, and glucose regulation after overnight fasting and during a mixed meal tolerance test (MMTT; 2 mL sweet/condensed milk) were measured before and after RYGB (RYGB+) or sham surgery (RYGB−). Results: HF/S feeding led to an increased body weight just before RYGB surgery, but it also caused enhanced weight loss following RYGB, which led to similar body weights in the HF/S and LF diet groups twenty-four days post-operatively. RYGB surgery and diet dependently and independently influenced meal-related parameter outcomes, where both RYGB+ and HF/S feeding resulted in shorter meal duration (p < 0.01), higher ingestion rates (p < 0.001), and increased satiety ratio (p < 0.05), especially in the HF/S diet group subjected to RYGB. While RYGB surgery generally improved baseline glycemic parameters including HOMA-IR (p < 0.01), it often interacted with diet to affect MMTT-induced hyperglycemia (p < 0.05), beta-cell sensitivity (p < 0.01), and the insulinogenic index (p < 0.01), with the LF rats overall maintaining better glycemic control than the HF/S-fed rats. Conclusions: This study shows the importance of controlling diet after RYGB surgery, as diet type significantly influences ingestive behavior, post-prandial glucose regulation, beta-cell sensitivity, and glucose tolerance after RYGB.

Male mice are frequently used for behavioral neuroscience research, but outcomes of behavioral tests are often variable across studies, contributing to poor reproducibility. Social housing conditions, social hierarchical status and within-cage order of testing are factors that likely influence behavioral outcomes, but it is unknown to what extent and if these factors interact. For this purpose, behavior of socially and individually housed male C57BL6/J mice was studied upon subjection to the open field test, the elevated plus-maze test and the three-chamber social test. In socially housed animals, effects of social hierarchical status and within-cage testing order were evaluated. We show that the differences in behavior outcomes between individually and socially housed mice depend on the social hierarchical status and the test order of the socially housed mice. Careful consideration of these factors in the design, analysis and interpretation of behavioral experiments with socially housed mice can lead to more precise results and more reliable research outcomes.

Diets varying in macronutrient composition, energy density, and/or palatability may cause differences in outcome of bariatric surgery. In the present study, rats feeding a healthy low-fat (LF) diet or an obesogenic high-fat/sucrose diet (HF/S) were either subjected to Roux-en-Y gastric bypass surgery (RYGB) or sham surgery, and weight loss trajectories and various energy balance parameters were assessed. Before RYGB, rats eating an HF/S (n = 14) diet increased body weight relative to rats eating an LF diet (n = 20; P < 0.01). After RYGB, absolute weight loss was larger in HF/S (n = 6) relative to LF feeding (n = 6) rats, and this was associated with reduced cumulative energy intake (EI; P < 0.05) and increased locomotor activity (LA; P < 0.05-0.001), finally leading to similar levels of reduced body fat content in HF/S and LF rats 3 wk after surgery. Regression analysis revealed that variation in RYGB-induced body weight loss was best explained by models including 1) postoperative cumulative EI and preoperative body weight (R2 = 0.87) and 2) postoperative cumulative EI and diet (R2 = 0.79), each without significant contribution of LA. Particularly rats on the LF diet became transiently more hypothermic and circadianally arrhythmic following RYGB (i.e., indicators of surgery-associated malaise) than HF/S feeding rats. Our data suggest that relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery, yet it promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.NEW & NOTEWORTHY Relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery in rats. Relative to feeding an LF diet, continued feeding an HF/S diet promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.

Background/Objectives: Personalized and self-initiated dietary adjustments have been shown to alleviate mental and somatic complaints. Here, we investigated the potential role of gut microbiome alterations underlying these effects. Methods: For this purpose, participants (n = 185) underwent a four-week self-initiated dietary intervention and filled out weekly questionnaires on their dietary intake, somatic and mental symptoms, and physical activity. Results: Overall, the participants lost weight, had alleviated mental and somatic complaints, reduced their total caloric and percentual carbohydrate intake, and ate less processed, party-type, and traditional Dutch food items, but ate more Pescatarian type food items, while keeping their fiber intake unaltered. Baseline and endpoint gut microbiota analyses using 16S rRNA gene sequencing revealed an overall increase in Gemmiger formicilis and reductions in Peptostreptococcaceae and Ruminococcus bromii over the four-week dietary intervention. While these bacterial alterations were considered to be beneficial for the host, they were not individually correlated with alterations in, or endpoint levels of, somatic and/or mental complaints. Instead, individual increases in Ruminococcus bicirculans (a well-known utilizer of plant cell wall polysaccharides) were strongly correlated with reductions in mental complaints, even though overall R. bicirculans remained unaltered over the course of the four-week self-initiated dierary intervention. Conclusions: Our results suggest that overall altered versus individually correlated microbiota abundances and their relations with host health characteristics over the course of a self-chosen dietary intervention may represent different levels of regulation, which remain to be further untangled.

Human milk beneficially affects infant growth and brain development. The supramolecular structure of lipid globules in human milk i.e., large lipid globules covered by the milk fat globule membrane, is believed to contribute to this effect, in addition to the supply of functional ingredients. Three preclinical (mouse) experiments were performed to study the effects of infant formula mimicking the supramolecular structure of human milk lipid globules on brain and metabolic health outcomes. From postnatal day 16 to 42, mouse offspring were exposed to a diet containing infant formula with large, phospholipid-coated lipid droplets (structure, STR) or infant formula with the same ingredients but lacking the unique structural properties as observed in human milk (ingredient, ING). Subsequently, in Study 1, the fatty acid composition in liver and brain membranes was measured, and expression of hippocampal molecular markers were analyzed. In Study 2 and 3 adult (Western-style diet-induced) body fat accumulation and cognitive function were evaluated. Animals exposed to STR compared to ING showed improved omega-3 fatty acid accumulation in liver and brain, and higher expression of brain myelin-associated glycoprotein. Early exposure to STR reduced fat mass accumulation in adulthood; the effect was more pronounced in animals exposed to a Western-style diet. Additionally, mice exposed to STR demonstrated better memory performance later in life. In conclusion, early life exposure to infant formula containing large, phospholipid-coated lipid droplets, that are closer to the supramolecular structure of lipid globules in human milk, positively affects adult brain and metabolic health outcomes in pre-clinical animal models.

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle β- oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.

The sub-diaphragmatic vagus innervates various organs involved in the control of glucose homeostasis including the liver, pancreas and the intestines. In the current study, we investigated the effect of acute electrical stimulation of the anterior trunk of the sub-diaphragmatic vagus on glucose fluxes in anaesthetized adult male rats. After overnight fast, rats underwent either vagus nerve stimulation (VNS+, n = 11; rectangular pulses at 5 Hz, 1.5 mA, 1 msec pulse width) or sham stimulation (VNS-; n = 11) for 120 min under isoflurane anesthesia. Before stimulation, the rats received an i.v. bolus of 1 mL/kg of a sterilized aqueous solution containing 125 mg/mL of D-[6,6-2H2] glucose. Endogenous glucose production (EGP) and glucose clearance rate (GCR) were calculated by kinetic analysis from the wash-out of injected D-[6,6-2H2]glucose from the circulation. VNS+ resulted in lower glucose levels compared to the VNS- group (p < 0.05), with similar insulin levels. EGP was similar in both groups, but the GCR was higher in the VNS+ group compared to the VNS- group (p < 0.001). Circulating levels of the sympathetic transmitter norepinephrine were reduced by VNS+ relative to VNS- treatment (p < 0.01). It is concluded that acute anterior sub-diaphragmatic VNS causes stimulation of peripheral glucose uptake, while plasma insulin levels remained similar, and this is associated with lower activity of the sympathetic nervous system.

The doubly labelled water (DLW) method is widely used to determine energy expenditure. In this work, we demonstrate the addition of the third stable isotope, 17O, to turn it into triply labelled water (TLW), using the three isotopes measurement of optical spectrometry. We performed TLW (2H, 18O and17O) measurements for the analysis of the CO2 production (rCO2) of mice on different diets for the first time. Triply highly enriched water was injected into mice, and the isotope enrichments of the distilled blood samples of one initial and two finals were measured by an off-axis integrated cavity output spectroscopy instrument. We evaluated the impact of different calculation protocols and the values of evaporative water loss fraction. We found that the dilution space and turnover rates of 17O and 18O were equal for the same mice group, and that values of rCO2 calculated based on 18O–2H, or on 17O–2H agreed very well. This increases the reliability and redundancy of the measurements and it lowers the uncertainty in the calculated rCO2 to 3% when taking the average of two DLW methods. However, the TLW method overestimated the rCO2 compared to the indirect calorimetry measurements that we also performed, much more for the mice on a high-fat diet than for low-fat. We hypothesize an extra loss or exchange mechanism with a high fractionation for 2H to explain this difference.

Breastfeeding (duration) can be positively associated with infant growth outcomes as well as improved cognitive functions during childhood and later life stages. (Prolonged) exposure to optimal lipid quantity and quality, i.e., the supramolecular structure of lipids, in mammalian milk, may contribute to these beneficial effects through nutritional early-life programming. In this pre-clinical study, we exposed male C57BL/6J mice from post-natal Days 16 to 42 (i.e., directly following normal lactation), to a diet with large lipid droplets coated with bovine milk fat globule membrane-derived phospholipids, which mimic more closely the supramolecular structure of lipid droplets in mammalian milk. We investigated whether exposure to this diet could affect growth and brain development-related parameters. As these outcomes are also known to be affected by the post-weaning social environment in mice, we included both individually housed and pair-wise housed animals and studied whether effects of diet were modulated by the social environment. After Day 42, all the animals were fed standard semi-synthetic rodent diet. Growth and body composition were assessed, and the mice were subjected to various behavioral tests. Individual housing attenuated adolescent growth, reduced femur length, and increased body fat mass. Adult social interest was increased due to individual housing, while cognitive and behavioral alterations as a result of different housing conditions were modest. The diet increased adolescent growth and femur length, increased lean body mass, reduced adolescent anxiety, and improved adult cognitive performance. These effects of diet exposure were comparable between individually and socially housed mice. Hence, early life exposure to a diet with lipid droplets that mimic the supramolecular structure of those in mammalian milk may improve adolescent growth and alters brain function in both socially and individually housed mice. These findings suggest that lipid structure in infant milk formula may be a relevant target for nutritional solutions, targeting both healthy infants and infants facing growth challenges.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is known to be associated with altered gastrointestinal function and microbiota composition. We previously showed that the gut bacteria harboring tyrosine decarboxylase enzymes interfere with levodopa, the main treatment for PD (S. P. van Kessel, A. K. Frye, A. O. El-Gendy, M. Castejon, A. Keshavarzian, G. van Dijk, and S. El Aidy, Nat Commun 10:310, 2019).

Abstract Ficus carica, (fig) one of the oldest plants cultivated on the earth, is rich in phytochemicals including organic acids, anthocyanins, phenolics, and phytosterols. Thus, the present research was carried out to explore the phytochemical composition of fig fruit extracts (prepared with 100% water and 70% ethanol) including, alkaloids, anthocyanins, flavonoids, and phenolic compounds along with HPLC characterization of flavonoids and phenolics. However, the prepared extract was also analyzed for its antioxidative capacity through ABTS, DPPH, FRAP, and H2O2. Extracts prepared with 70% ethanol have better total alkaloids, flavonoids, and phenolics concentration, whereas 100% aqueous extract was more efficient to extract total anthocyanins. HPLC quantification of flavonoids and phenolics showed fig fruit is a good amount of catechin (ranged from 20.89 to 23.97 mg/100g), flavanone (ranged from 8.79 to 12.49 mg/100g), and gallic acid (ranged from 32.52 to 33.350 mg/100g). Likewise, the extract having higher phytochemical concentration exhibited higher antioxidant activity. Conclusively, the results depict nutritional composition as a function of genetic makeup and ecological conditions. The current study suggests that commercially available fig (especially Afghani) and its ethanolic extract possess substantial phytochemical compounds having antioxidant potential. Thus, fig may act as a functional food or nutraceutical ingredient having the potential to alleviate oxidative stress-mediated diseases.

The risk for development of non-communicable diseases (NCDs) can be predicted by somatic or mental symptoms and dietary alterations aimed at improvement of those symptoms could potentially delay development of NCDs. The goal of this study was to identify whether self-initiated dietary changes could reduce mental and somatic symptoms in relatively healthy individuals. Participants (n = 494) recruited from the Dutch population filled out weekly questionnaires on dietary intake, somatic and mental symptoms and physical activity at baseline and during dieting for four weeks. There was a significant reduction in mental and somatic symptoms, body weight, and waist circumference at four weeks, whereas physical activity remained unchanged. Five dietary patterns were identified by principal component analysis labelled "Processed foods", "Animal source foods", "Wheel of Five", "Traditional Dutch", and "Party". Reduction in mental symptoms was correlated to increased physical activity and increased intake of Wheel of Five foods. Reduction in somatic symptoms was correlated to body weight loss and less Processed foods, more Wheel of Five foods, and lower intake of fat and protein. Higher intake of protein and fat and lower intake of carbohydrates, however, were correlated to body weight loss. In conclusion this research showed that a self-initiated dietary change can lead to a significant reduction of mental and somatic symptoms.

BACKGROUND: Lifelong consumption of a Western-style diet is a risk factor for developing metabolic disorders and therefore impairs healthy aging. Dietary restriction (DR) could delay the onset of age-related diseases and prolong life span, however, the extent to which this depends on diet type is poorly understood. OBJECTIVE: To study whether feeding a Western-style diet affects the healthy aging benefits of DR. METHODS: Mice fed a Western-style diet (ad libitum and DR) were compared to those fed a standard healthy diet (ad libitum and DR). Survival and several metabolic and endocrine parameters were analyzed. RESULTS: Lifelong consumption of a Western-style diet resulted in increased adiposity, elevated triglyceride levels in plasma, higher homeostatic model assessment-insulin resistance and higher resting metabolic rate in mice compared to the standard diet group. This was accompanied by reduced survival in the Western-style diet group. DR irrespective of diet type improved abovementioned parameters. CONCLUSIONS: Lifelong restricted consumption of Western-style diet led to improved metabolic and endocrine parameters, and increased survival compared to the ad libitum Western-style diet group. Interestingly, the survival was comparable in restricted Western-style and standard diet groups, suggesting that reduced food intake rather than diet composition play more important role in promoting longevity/survival.

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.

Accumulating evidence implicates gut-microbiota-derived metabolites as important regulators of host energy balance and fuel homeostasis, the underlying mechanisms are currently subject to intense research. In this review, the most important executors, short chain fatty acids, which both directly and indirectly fulfill the interactions between gut microbiota and host will be discussed. Distinct roles of individual short chain fatty acids and the different effects they exert on host metabolism have long been overlooked, which compromises the process of clarifying the sophisticated crosstalk between gut microbiota and its host. Moreover, recent findings suggest that exogenously administered short chain fatty acids affect host metabolism via different mechanisms depending on the routes they enter the host. Although these exogenous routes are often artificial, they may help to comprehend the roles of the short-chain-fatty-acid mechanisms and signaling sites, that would normally occur after intestinal absorption of short chain fatty acids. Cautions should be addressed of generalizing findings, since different results have appeared in different host species, which may imply a host species-specific response to short chain fatty acids.

The metabolic syndrome (MetS) comprises cardiometabolic risk factors frequently found in individuals with obesity. Guidelines to prevent or reverse MetS suggest limiting fat intake, however, lowering carbohydrate intake has gained attention too. The aim for this review was to determine to what extent either weight loss, reduction in caloric intake, or changes in macronutrient intake contribute to improvement in markers of MetS in persons with obesity without cardiometabolic disease. A meta-analysis was performed across a spectrum of studies applying low-carbohydrate (LC) and low-fat (LF) diets. PubMed searches yielded 17 articles describing 12 separate intervention studies assessing changes in MetS markers of persons with obesity assigned to LC (<40% energy from carbohydrates) or LF (<30% energy from fat) diets. Both diets could lead to weight loss and improve markers of MetS. Meta-regression revealed that weight loss most efficaciously reduced fasting glucose levels independent of macronutrient intake at the end of the study. Actual carbohydrate intake and actual fat intake at the end of the study, but not the percent changes in intake of these macronutrients, improved diastolic blood pressure and circulating triglyceride levels, without an effect of weight loss. The homeostatic model assessment of insulin resistance improved with both diets, whereas high-density lipoprotein cholesterol only improved in the LC diet, both irrespective of aforementioned factors. Remarkably, changes in caloric intake did not play a primary role in altering MetS markers. Taken together, these data suggest that, beyond the general effects of the LC and LF diet categories to improve MetS markers, there are also specific roles for weight loss, LC and HF intake, but not reduced caloric intake, that improve markers of MetS irrespective of diet categorization. On the basis of the results from this meta-analysis, guidelines to prevent MetS may need to be re-evaluated.

Post-bariatric hypoglycemia is a complication of bariatric surgery, especially Roux-en-Y gastric bypass (RYGB). The counterregulatory hormonal and sympathetic neural responses were measured during a previously reported meal test in which 48% had an almost asymptomatic hypoglycemic event. Forty-four randomly selected patients 4 years after RYGB. A liquid meal test (MMT) after overnight fasting. Based on the glucose nadir during the MMT, patients were divided in a hypo group (glucose < 3.3 mmol/L) and a non-hypo group (glucose ≥ 3.3 mmol/L). Cortisol, epinephrine, norepinephrine, blood pressure, and heart rate were measured up to 180 min after ingestion of the meal. Incremental areas under the curve (iAUC), peak, and delta hormone responses after the glucose nadir were calculated. Parameters were compared between the hypo and non-hypo groups. A total of 21/44 (48%) had an almost asymptomatic hypoglycemic event. Cortisol and epinephrine responses in the hypo group were not increased compared to the non-hypo group, and there were no signs of increased sympathetic nerve activity. Peak and delta cortisol were lower in the hypo compared to the non-hypo group. Norepinephrine was higher in the hypo group especially in the time frame 60–120 and 120–180 min after start of the meal. No increase in epinephrine and a lower cortisol response to hypoglycemia were observed compared to normoglycemia during a meal test in patients after RYGB. Norepinephrine levels were higher in the hypo group. These findings may suggest that possible recurrent hypoglycemia after RYGB results in blunting of counterregulatory responses indicative of hypoglycemia-induced autonomic failure. ISRCTN 11738149.