Far from the walking pace. Ecological and evolutionary consequences of the suboptimal locomotion speeds in non-adult humans.

INTRODUCTION: Locomotion activities are part of most human daily tasks and are the basis for subsistence activities, particularly for hunter-gatherers. Therefore, differences in speed walking-related variables may have an effect, not only on the mobility of the group, but also on its composition. Some anthropometric parameters related to body length could affect walking speed-related variables and contribute to different human behaviors. However, there is currently little information on the influence of these parameters in nonadult individuals. METHODS: Overall, 11 females and 17 male child/adolescents, 8-17 years of age, volunteered to participate in this cross-sectional study. Five different pace walking tests were performed on a treadmill to calculate the optimal locomotion speed (OLS) and U-shaped relationship between the walking energy expenditure and speed (χ2 cost of transport [CoT]) (i.e., energetic walking flexibility). RESULTS: The mean OLS was 3.05 ± 0.13 miles per hour (mph), with no differences between sexes. Similarly, there were no sex differences in walking flexibility according to the χ2 CoT. Body height (p < .0001) and femur length (p < .001) were positively correlated with χ2 CoT; however, female child/adolescents mitigated the effect of height and femur length when walking at suboptimal speeds. CONCLUSION: Consistent with prior observations in adults, our findings suggest that anthropometric parameters related to body stature are associated with reduced suboptimal walking flexibility in children and adolescents. Taken together, these results suggest that children and adolescents can adapt their pace to the one of taller individuals without a highly energetic penalty, but this flexibility decreases with increasing body size.

Validation of predictive equations to estimate resting metabolic rate of females and males across different activity levels.

OBJECTIVES: Using equations to predict resting metabolic rate (RMR) has yielded different degrees of validity, particularly when sex and different physical activity levels were considered. Therefore, the purpose of the present study was to determine the validity of several different predictive equations to estimate RMR in female and male adults with varying physical activity levels. METHOD: We measured the RMR of 50 adults (26 females and 24 males) evenly distributed through activity levels varying from sedentary to ultra-endurance. Body composition was measured by dual X-ray absorptiometry and physical activity was monitored by accelerometry. Ten equations to predict RMR were applied (using Body Mass [BM]: Harris & Benedict, 1919; Mifflin et al., 1990 [MifflinBM]; Pontzer et al., 2021 [PontzerBM]; Schofield, 1985; FAO/WHO/UNU, 2004; and using Fat-Free Mass (FFM): Cunningham, 1991; Johnstone et al., 2006; Mifflin et al., 1990 [MifflinFFM]; Nelson et al. 1992; Pontzer et al., 2021 [PontzerFFM]). The accuracy of these equations was analyzed, and the effect of sex and physical activity was evaluated using different accuracy metrics. RESULTS: Equations using BM were less accurate for females, and their accuracy was influenced by physical activity and body composition. FFM equations were slightly less accurate for males but there was no obvious effect of physical activity or other sample parameters. PontzerFFM provides higher accuracy than other models independent of the magnitude of RMR, sex, activity levels, and sample characteristics. CONCLUSION: Equations using FFM were more accurate than BM equations in our sample. Future studies are needed to test the accuracy of RMR prediction equations in diverse samples.

Endothelial-derived extracellular vesicles from obese/hypertensive adults increase factors associated with hypertrophy and fibrosis in cardiomyocytes.

Obesity and hypertension, independently and combined, are associated with increased risk of heart failure and heart failure-related morbidity and mortality. Interest in circulating endothelial cell-derived microvesicles (EMVs) has intensified because of their involvement in the development and progression of endothelial dysfunction, atherosclerosis, and cardiomyopathy. The experimental aim of this study was to determine, in vitro, the effects of EMVs isolated from obese/hypertensive adults on key proteins regulating cardiomyocyte hypertrophy [cardiac troponin T (cTnT), α-actinin, nuclear factor-kB (NF-kB)] and fibrosis [transforming growth factor (TGF)-ß, collagen1-α1], as well as endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production. EMVs (CD144+ microvesicles) were isolated from plasma by flow cytometry in 12 normal weight/normotensive [8 males/4 females; age: 56 ± 5 yr; body mass index (BMI): 23.3 ± 2.0 kg/m2; blood pressure (BP): 117/74 ± 4/5 mmHg] and 12 obese/hypertensive (8 males/4 females; 57 ± 5 yr; 31.7 ± 1.8 kg/m2; 138/83 ± 8/7 mmHg) adults. Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were cultured and treated with EMVs from either normal weight/normotensive or obese/hypertensive adults for 24 h. Expression of cTnT (64.1 ± 13.9 vs. 29.5 ± 7.8 AU), α-actinin (66.0 ± 14.7 vs. 36.2 ± 10.3 AU), NF-kB (166.3 ± 13.3 vs. 149.5 ± 8.8 AU), phosphorylated-NF-kB (226.1 ± 25.2 vs. 179.1 ± 25.5 AU), and TGF-ß (62.1 ± 13.3 vs. 23.5 ± 8.8 AU) were significantly higher and eNOS activation (16.4 ± 4.3 vs. 24.8 ± 3.7 AU) and nitric oxide production (6.8 ± 1.2 vs. 9.6 ± 1.3 µmol/L) were significantly lower in iPSC-CMs treated with EMVs from obese/hypertensive compared with normal weight/normotensive adults. These data indicate that EMVs from obese/hypertensive adults induce a cardiomyocyte phenotype prone to hypertrophy, fibrosis, and reduced nitric oxide production, central factors associated with heart failure risk and development.NEW & NOTEWORTHY In the present study we determined the effect of endothelial microvesicles (EMVs) isolated from obese/hypertensive adults on mediators of cardiomyocyte hypertrophy [cardiac troponin T (cTnT), α-actinin, nuclear factor-kB (NF-kB)] and fibrosis [transforming growth factor (TGF-ß), collagen1-α1] as well as endothelial nitric oxide synthase (eNOS) expression and NO production. EMVs from obese/hypertensive induced significantly higher expression of hypertrophic (cTnT, α-actinin, NF-kB) and fibrotic (TGF-ß) proteins as well as significantly lower eNOS activation and NO production in cardiomyocytes than EMVs from normal weight/normotensive adults. EMVs are a potential mediating factor in the increased risk of cardiomyopathy and heart failure with obesity/hypertension.

Initiation of 3,3-dimethyl-1-butanol at midlife prevents endothelial dysfunction and attenuates in vivo aortic stiffening with ageing in mice.

Vascular dysfunction: develops progressively with ageing; increases the risk of cardiovascular diseases (CVD); and is characterized by endothelial dysfunction and arterial stiffening, which are primarily mediated by superoxide-driven oxidative stress and consequently reduced nitric oxide (NO) bioavailability and arterial structural changes. Interventions initiated before vascular dysfunction manifests may have more promise for reducing CVD risk than interventions targeting established dysfunction. Gut microbiome-derived trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk, and can be suppressed by 3,3-dimethyl-1-butanol (DMB). We investigated whether DMB supplementation could prevent age-related vascular dysfunction in C57BL/6N mice when initiated prior to development of dysfunction. Mice received drinking water with 1% DMB or normal drinking water (control) from midlife (18 months) until being studied at 21, 24 or 27 months of age, and were compared to young adult (5 month) mice. Endothelial function [carotid artery endothelium-dependent dilatation (EDD) to acetylcholine; pressure myography] progressively declined with age in control mice, which was fully prevented by DMB via higher NO-mediated EDD and lower superoxide-related suppression of EDD (normalization of EDD with the superoxide dismutase mimetic TEMPOL). In vivo aortic stiffness (pulse wave velocity) increased progressively with age in controls, but DMB attenuated stiffening by ∼ 70%, probably due to preservation of endothelial function, as DMB did not affect aortic intrinsic mechanical (structural) stiffness (stress-strain testing) nor adventitial abundance of the arterial structural protein collagen. Our findings indicate that long-term DMB supplementation prevents/attenuates age-related vascular dysfunction, and therefore has potential for translation to humans for reducing CV risk with ageing. KEY POINTS: Vascular dysfunction, characterized by endothelial dysfunction and arterial stiffening, develops progressively with ageing and increases the risk of cardiovascular diseases (CVD). Interventions aimed at preventing the development of CV risk factors have more potential for preventing CVD relative to those aimed at reversing established dysfunction. The gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk and can be suppressed by supplementation with 3,3-dimethyl-1-butanol (DMB). In mice, DMB prevented the development of endothelial dysfunction and delayed and attenuated in vivo arterial stiffening with ageing when supplementation was initiated in midlife, prior to the development of dysfunction. DMB supplementation or other TMAO-suppressing interventions have potential for translation to humans for reducing CV risk with ageing.

The Validity of Urine Color as a Hydration Biomarker within the General Adult Population and Athletes: A Systematic Review.

Frequent monitoring of hydration status may help to avoid the adverse effects of dehydration. Other than urine color assessment, hydration assessment methods are largely impractical for the general population and athletes to implement on a routine basis. Despite its widespread use, the validity of urine color as an indicator of hydration status has not been systematically evaluated. The objective of this systematic review is to determine the validity of urine color evaluation as a hydration status assessment method in the general adult population, older adults, and athletes. Using the PRISMA guidelines, electronic databases were searched to identify original research articles of all study design types for inclusion. Of the 424 articles screened, 10 met inclusion criteria. Most studies compared urine color to either urinary specific gravity or urine osmolality, and reported significant associations (r) ranging from 0.40 to 0.93. Lower correlations were noted in studies of adults aged >60 years. Studies generally reported a high sensitivity of urine color as a diagnostic tool for detecting dehydration and supported the ability of this method to distinguish across categories of hydration status. Research is needed to determine if clinicians, patients, and clients can accurately utilize this method in clinical and real-world settings. Future research is also needed to extend these findings to other populations, such as children.Key teaching pointsInadequate hydration can lead to impairments in physical performance and cognitive function.Methods used to assess hydration status include plasma/serum osmolality, urinary specific gravity (USG), urine osmolality (Uosm), change in body weight, urine volume, and urine color.Urine color assessment is a practical method that is routinely used in clinical, athletic, and other settings. The validity of this method has not been systemically evaluated.Available research was limited to 10 articles.Validity of this method was generally supported; however, research has not investigated the validity of this method by clinicians, patients and clients.

Evaluation of Pragmatic Methods to Rapidly Assess Habitual Beverage Intake and Hydration Status in U.S. Collegiate Athletes.

Fluid intake recommendations have been established for the athletic population in order to promote adequate hydration. The Beverage Intake Questionnaire (BEVQ-15) is a quick and reliable food frequency questionnaire that quantifies habitual beverage intake, which has been validated in children, adolescents, and adults. However, no validated beverage consumption questionnaire is available for collegiate athletes. Urine color (UC), while feasible for determining hydration status, has not been validated within a variety of collegiate athletes. The purpose of this investigation was to evaluate the comparative validity and reliability of pragmatic methods to rapidly assess BEVQ-15 and UC rating in U.S. Division I collegiate athletes. Student-athletes (n = 120; 54% females; age 19 ± 1 years) from two universities were recruited to complete three study sessions. At the first and third sessions, the participants completed the BEVQ-15 and provided a urine sample to determine UC and urinary specific gravity. All sessions included completion of a 24-hr dietary recall. Total fluid intake (fl oz) was 111 ± 107 and 108 ± 42 using the BEVQ-15 and the mean of three 24-hr dietary recalls, respectively, which was not different between methods (p > .05). There were moderate associations between the BEVQ-15 and dietary recall results for total beverage intake fl oz and kcal(r = .413 and r = 4.65; p ≤ .05, respectively). Strong associations were noted between both researcher-rated and participant-rated UC with urinary specific gravity measures (r = .675 and r = .884; p ≤ .05, respectively). Therefore, these rapid assessment methods demonstrated acceptable validity and may be used as practical methods to determine whether athletes are meeting their hydration recommendations.

Effects of Seasonal Vitamin D3 Supplementation on Strength, Power, and Body Composition in College Swimmers.

The purpose of this study was to evaluate the impact of fall season vitamin D3 supplementation on strength/power, body composition, and anabolic hormones in swimmers with optimal vitamin D status at summer's end. Male and female National Collegiate Athletic Association Division I swimmers (N = 19) with optimal 25-hydroxyvitamin D [25(OH)D] randomly received 5,000 IU of vitamin D3 (VITD) or placebo (PLA) daily for 12 weeks while participating in swimming and strength and conditioning training (August-November). Before and after the intervention, the participants underwent blood sampling for analysis of serum 25(OH)D, parathyroid hormone, total testosterone, free testosterone, sex hormone-binding globulin, and insulin-like growth factor 1, dual-energy X-ray absorptiometry, and strength/power testing (bench press, squat, dead lift, standing broad jump, vertical jump, and dips and pull-ups). Sex was used as a covariate for analyses. The 25(OH)D was decreased by 44% in PLA (p < .05) and increased by 8% in VITD over the 12 weeks. Fat-free mass increased in VITD (56.4-59.1 kg; p < .05), but not PLA (59.4-59.7 kg; p < .01). Significant Group × Time interaction effects were observed for dead lift (F = 21.577, p < .01) and vertical jump (F = 11.219, p < .01), but no other strength/power tests. Total testosterone decreased similarly in both groups, but free testosterone decreased and sex hormone-binding globulin increased only in PLA (p < .01). There were no group differences or changes in insulin-like growth factor 1 with the intervention. The findings suggest that vitamin D supplementation is an efficacious strategy to maintain 25(OH)D during the fall season training and to enhance some aspects of strength/power and fat-free mass in swimmers. Further research on the relationship between vitamin D and anabolic hormones is needed.

Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice.

KEY POINTS: Age-related arterial dysfunction, characterized by oxidative stress- and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age-related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad-spectrum, poorly-absorbed antibiotics in drinking water for 3-4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age-related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide. The results of the present study provide the first proof-of-concept evidence that the gut microbiome is an important mediator of age-related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. ABSTRACT: Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4 weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m  s-1  vs. OC: 4.43 ± 0.38 m  s-1 ; vs. OA: 3.52 ± 0.35 m  s-1 ; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 µmol  L-1   vs. OC: 7.2 ± 2.0 µmol  L-1 ; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 µmol  L-1 ; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.

Pre-meal inulin consumption does not affect acute energy intake in overweight and obese middle-aged and older adults: A randomized controlled crossover pilot trial.

BACKGROUND: Three-fourths of adults older than 55 years in the United States are overweight or obese. Prebiotics including inulin-type fructans may benefit with weight management. AIM: We aimed to investigate the acute effects of pre-meal inulin consumption on energy intake (EI) and appetite in older adults. METHODS: Sedentary, overweight or obese middle-aged and older adults ( n = 7, 60.9 ± 4.4 years, BMI 32.9 ± 4.3 kg/m2) ingested inulin (10 g) or a water preload before each test period in a randomly assigned order. EI, appetite and gastrointestinal symptoms were monitored during the following 24 h. RESULTS: No differences in EI were noted between conditions (inulin: 14744 ± 5552 kJ, control: 13924 ± 4904 kJ, p > 0.05). Rumbling was increased with inulin consumption ( p < 0.05). CONCLUSION: Pre-meal inulin consumption does not acutely decrease EI or suppress appetite in older adults. Further research should address individual differences among diets, eating behaviors, and microbiota profiles.

Representation of adults with class III obesity in studies assessing validity of self-reported energy intake using doubly labeled water: A systematic review.

The measurement of habitual energy intake remains a challenge in nutrition research. High levels of misreporting, particularly among adults with obesity, have been observed when comparing self-reported energy intake to energy expenditure assessed via the doubly labeled water technique. Little is known about misreporting in adults with class III obesity (body mass index ≥40 kg/m2). This systematic review assessed the representation of adults with class III obesity in dietary validation studies and the validity of self-reported dietary energy intake for this group. Studies were included in this review if they: compared self-reported energy intake assessment method(s) to doubly labeled water, had participants ≥18 years old, and included participants with class III obesity. Fifteen studies met these criteria. Of those, eight included information about the number of participants with class III obesity. Out of 1784 participants across eight studies, 63 (3.5%) participants had class III obesity, compared to 9.2% of US adults with class III obesity. Six studies provided data on validity of energy intake assessment for class III obesity, with five of these showing underreporting. Participants with class III obesity are underrepresented in dietary validation studies. Future research should explore the role of weight status on dietary reporting accuracy.

Acute effect of an exogenous ketone monoester supplement on appetite and food intake in adults with type 2 diabetes.

The effects of exogenous ketones on appetite and food intake remain elusive, especially for people with type 2 diabetes (T2D). This study aimed to determine whether acute ingestion of an oral ketone monoester supplement (KME) affected appetite sensations, prospective food consumption and intake in T2D. Results showed that acute KME ingestion did not significantly alter appetite scores. However, there was a tendency for lower energy intake during an ad libitum meal 3 h following ketone ingestion compared to non-energetic placebo. Further research is warranted to understand the long-term effects of exogenous ketones for energy and macronutrient intake in T2D.

Ultra-processed food intake, gut microbiome, and glucose homeostasis in mid-life adults: Background, design, and methods of a controlled feeding trial.

BACKGROUND: Aging is associated with gut dysbiosis, low-grade inflammation, and increased risk of type 2 diabetes (T2D). Prediabetes, which increases T2D and cardiovascular disease risk, is present in 45-50% of mid-life adults. The gut microbiota may link ultra-processed food (UPF) with inflammation and T2D risk. METHODS: Following a 2-week standardized lead-in diet (59% UPF), adults aged 40-65 years will be randomly assigned to a 6-week diet emphasizing either UPF (81% total energy) or non-UPF (0% total energy). Measurements of insulin sensitivity, 24-h and postprandial glycemic control, gut microbiota composition/function, fecal short chain fatty acids, intestinal inflammation, inflammatory cytokines, and vascular function will be made before and following the 6-week intervention period. Prior to recruitment, menus were developed in order to match UPF and non-UPF conditions based upon relevant dietary factors. Menus were evaluated for palatability and costs, and the commercial additive content of study diets was quantified to explore potential links with outcomes. RESULTS: Overall diet palatability ratings were similar (UPF = 7.6 ± 1.0; Non-UPF = 6.8 ± 1.5; Like Moderately = 7, Like Very Much = 8). Cost analysis (food + labor) of the 2000 kcal menu (7-d average) revealed lower costs for UPF compared to non-UPF diets ($20.97/d and $40.23/d, respectively). Additive exposure assessment of the 2000 kcal UPF diet indicated that soy lecithin (16×/week), citric acid (13×/week), sorbic acid (13×/week), and sodium citrate (12×/week) were the most frequently consumed additives. CONCLUSIONS: Whether UPF consumption impairs glucose homeostasis in mid-life adults is unknown. Findings will address this research gap and contribute information on how UPF consumption may influence T2D development.

Validity of predictive equations for total energy expenditure against doubly labeled water.

Variations in physical activity energy expenditure can make accurate prediction of total energy expenditure (TEE) challenging. The purpose of the present study was to determine the accuracy of available equations to predict TEE in individuals varying in physical activity (PA) levels. TEE was measured by DLW in 56 adults varying in PA levels which were monitored by accelerometry. Ten different models were used to predict TEE and their accuracy and precision were evaluated, considering the effect of sex and PA. The models generally underestimated the TEE in this population. An equation published by Plucker was the most accurate in predicting the TEE in our entire sample. The Pontzer and Vinken models were the most accurate for those with lower PA levels. Despite the levels of accuracy of some equations, there were sizable errors (low precision) at an individual level. Future studies are needed to develop and validate these equations.

The influence of ultra-processed food consumption on reward processing and energy intake: Background, design, and methods of a controlled feeding trial in adolescents and young adults.

BACKGROUND: The greatest age-related weight gain occurs in the early/mid-20s. Overall dietary quality among adolescents and emerging adults (age 18-25) is poor, with ultra-processed foods (UPF) representing more than two-thirds of adolescents' total energy intake (i.e., 68%). UPF consumption may impact cognitive and neurobiological factors that influence dietary decision-making and energy intake (EI). To date, no research has addressed this in this population. METHODS: Participants aged 18-25 will undergo two 14-day controlled feeding periods (81% UPF, 0% UPF) using a randomly assigned crossover design, with a 4-week washout between conditions. Brain response to a UPF-rich milkshake, as well as behavioral measures of executive function, will be evaluated before and after each diet. Following each diet, measurements include ad libitum buffet meal EI, food selection, eating rate, and eating in the absence of hunger (EAH). Prior to initiating recruitment, controlled diet menus, buffet, and EAH snacks were developed and evaluated for palatability. Sensory and texture attributes of buffet and EAH snack foods were also evaluated. RESULTS: Overall diet palatability was rated "like very much" (8)/"like moderately"(7) (UPF: 7.6 ± 1.0; Non-UPF: 6.8 ± 1.5). Subjective hardness rating (range = 1-9 [1 = soft, 9 = hard] was similar between UPF and Non-UPF buffet and snack items (UPF:4.22 ± 2.19, Non-UPF: 4.70 ± 2.03), as was the objective measure of hardness (UPF: 2874.33 ± 2497.06 g, Non-UPF: 2243.32 ± 1700.51 g). CONCLUSIONS: Findings could contribute to an emerging neurobiological understanding of the effects of UPF consumption including energy overconsumption and weight gain among individuals at a critical developmental stage.

Suppression of trimethylamine N-oxide with DMB mitigates vascular dysfunction, exercise intolerance, and frailty associated with a Western-style diet in mice.

Consumption of a Western-style diet (WD; high fat, high sugar, low fiber) is associated with impaired vascular function and increased risk of cardiovascular diseases (CVD), which could be mediated partly by increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). We investigated if suppression of TMAO with 3,3-dimethyl-1-butanol (DMB; inhibitor of microbial TMA lyase) in mice could prevent: 1) WD-induced vascular endothelial dysfunction and aortic stiffening and 2) WD-induced reductions in endurance exercise tolerance and increases in frailty, as both are linked to WD, vascular dysfunction, and increased CVD risk. C57BL/6N mice were fed standard chow or WD (41% fat, ∼25% sugar, 4% fiber) for 5 mo beginning at ∼2 mo of age. Within each diet, mice randomly received (n = 11-13/group) normal drinking water (control) or 1% DMB in drinking water for the last 8 wk (from 5 to 7 mo of age). Plasma TMAO was increased in WD-fed mice but suppressed by DMB. WD induced endothelial dysfunction, assessed as carotid artery endothelium-dependent dilation to acetylcholine, and progressive increases in aortic stiffness (measured serially in vivo as pulse wave velocity), both of which were fully prevented by supplementation with DMB. Endurance exercise tolerance, assessed as time to fatigue on a rotarod test, was impaired in WD-fed mice but partially recovered by DMB. Lastly, WD-induced increases in frailty (31-point index) were prevented by DMB. Our findings indicate DMB or other TMAO-lowering therapies may be promising for mitigating the adverse effects of WD on physiological function, and thereby reducing risk of chronic diseases.NEW & NOTEWORTHY We provide novel evidence that increased circulating concentrations of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) contribute to vascular dysfunction associated with consumption of a Western-style diet and that this dysfunction can be prevented by suppressing TMAO with DMB, thereby supporting translation of this compound to humans. Furthermore, to our knowledge, we present the first evidence of the role of TMAO in mediating impairments in endurance exercise tolerance and increased frailty in any context.

Fasting and postprandial trimethylamine N-oxide in sedentary and endurance-trained males following a short-term high-fat diet.

Gut bacteria release trimethylamine (TMA) from dietary substrates. TMA is absorbed and is subsequently oxidized in the liver to produce trimethylamine N-oxide (TMAO). Plasma TMAO levels are positively correlated with risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). High-fat diet (HFD) consumption has been reported to increase fasting and postprandial TMAO in sedentary individuals. However, whether the increase in TMAO with consumption of an HFD is observed in endurance-trained males is unknown. Healthy, sedentary (n = 17), and endurance-trained (n = 7) males consumed a 10-day eucaloric diet comprised of 55% carbohydrate, 30% total fat, and <10% saturated fat prior to baseline testing. Blood samples were obtained in a fasted state and for a 4-hour high-fat challenge (HFC) meal at baseline and then again following 5-day HFD (30% carbohydrate, 55% total fat, and 25% saturated fat). Plasma TMAO and TMA-moiety (choline, betaine, L-carnitine) concentrations were measured using isocratic ultraperformance liquid chromatography-tandem mass spectrometry. Age (23 ±3 vs. 22 ± 2 years) and body mass index (23.0 ± 3.0 vs. 23.5 ± 2.1 kg/m2 ) were similar (both p > 0.05) in the sedentary and endurance-trained group, respectively. VO2max was significantly higher in the endurance-trained compared with sedentary males (56.7 ± 8.2 vs. 39.9 ± 6.0 ml/kg/min). Neither the HFC nor the HFD evoked a detectable change in plasma TMAO (p > 0.05) in either group. Future studies are needed to identify the effects of endurance training on TMAO production.

Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation.

Trimethylamine-N-oxide (TMAO) has been reported as a risk factor for atherosclerosis development, as well as for other cardiovascular disease (CVD) pathologies. The objective of this review is to provide a useful summary on the use of phytochemicals as TMAO-reducing agents. This review discusses the main mechanisms by which TMAO promotes CVD, including the modulation of lipid and bile acid metabolism, and the promotion of endothelial dysfunction and oxidative stress. Current knowledge on the available strategies to reduce TMAO formation are discussed, highlighting the effect and potential of phytochemicals. Overall, phytochemicals (i.e., phenolic compounds or glucosinolates) reduce TMAO formation by modulating gut microbiota composition and/or function, inhibiting host's capacity to metabolize TMA to TMAO, or a combination of both. Perspectives for design of future studies involving phytochemicals as TMAO-reducing agents are discussed. Overall, the information provided by this review outlines the current state of the art of the role of phytochemicals as TMAO reducing agents, providing valuable insight to further advance in this field of study.

Prebiotic Inulin Supplementation and Peripheral Insulin Sensitivity in adults at Elevated Risk for Type 2 Diabetes: A Pilot Randomized Controlled Trial.

Prediabetes affects 84.1 million adults, and many will progress to type 2 diabetes (T2D). The objective of this proof-of-concept trial was to determine the efficacy of inulin supplementation to improve glucose metabolism and reduce T2D risk. Adults (n = 24; BMI: 31.3 ± 2.9 kg/m2; age: 54.4 ± 8.3 years) at risk for T2D were enrolled in this controlled feeding trial and consumed either inulin (10 g/day) or placebo (maltodextrin, 10 g/day) for six weeks. Assessments included peripheral insulin sensitivity, fasting glucose, and insulin, HOMA-IR, in vivo skeletal muscle substrate preference, Bifidobacteria copy number, intestinal permeability, and endotoxin concentrations. Participant retention was 92%. There were no baseline group differences except for fasting insulin (p = 0.003). The magnitude of reduction in fasting insulin concentrations with inulin (p = 0.003, inulin = Δ-2.9, placebo = Δ2.3) was attenuated after adjustment for baseline concentrations (p = 0.04). After adjusting for baseline values, reduction in HOMA-IR with inulin (inulin = Δ-0.40, placebo=Δ0.27; p = 0.004) remained significant. Bifidobacteria 16s increased (p = 0.04; inulin = Δ3.1e9, placebo = Δ-8.9e8) with inulin supplementation. Despite increases in gut Bifidobacteria, inulin supplementation did not improve peripheral insulin sensitivity. These findings question the need for larger investigations of inulin and insulin sensitivity in this population.

Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans.

[Figure: see text].

Postprandial skeletal muscle metabolism following a high-fat diet in sedentary and endurance-trained males.

Our objective was to determine the influence of a high-fat diet (HFD) on fasting and postprandial skeletal muscle substrate metabolism in endurance-trained (ET) compared with sedentary (SED) humans. SED (n = 17) and ET (n = 7) males were control-fed a 10-day moderate-fat diet followed by a 5-day isocaloric HFD (55% fat, 30% carbohydrate). Skeletal muscle biopsies were taken in the fasted condition and 4 h after a high-fat meal (820 kcals; 63% fat and 25% carbohydrate). Palmitate-induced suppression of pyruvate oxidation, an indication of substrate preference, and oxidation of fat and glucose were measured in homogenized skeletal muscle in fasted and fed states. Postprandial responses were calculated as percent changes from fasting to fed states. Postprandial suppression of pyruvate oxidation was maintained after the HFD in ET, but not SED skeletal muscle, suggesting greater adaptability to dietary intake changes in the former. Fasting total fat oxidation increased due to the HFD in ET skeletal muscle (P = 0.006), which was driven by incomplete fat oxidation (P = 0.008). Fasting fat oxidation remained unchanged in skeletal muscle of SED individuals. Yet, postprandial fat oxidation was similar between groups. Fasting glucose oxidation was elevated after the HFD in ET (P = 0.036), but not SED, skeletal muscle. Postprandial glucose oxidation was reduced due to the HFD in SED (P = 0.002), but not ET, skeletal muscle. These findings provide insight into differing substrate metabolism responses between SED and ET individuals and highlight the role that the prevailing diet may play in modulating fasting and postprandial metabolic responses in skeletal muscle.NEW & NOTEWORTHY The relationship between high dietary fat intake and physical activity level and their combined effect on skeletal muscle substrate metabolism remains unclear. We assessed the influence of the prevailing diet in modulating substrate oxidation in skeletal muscle of endurance-trained compared with sedentary humans during a high-fat challenge meal. Collectively, our findings demonstrate the adaptability of skeletal muscle in endurance-trained individuals to high dietary fat intake.