Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

The emerging field of precision nutrition is based on the notion that inter-individual responses across diets of different calorie-macronutrient content may contribute to inter-individual differences in metabolism, adiposity, and weight gain. Free-living diet studies have been traditionally challenged by difficulties in controlling adherence to prescribed calories and macronutrient content and rarely allow a period of metabolic stability prior to metabolic measures (to minimize influences of weight changes). In this context, key physiologic measures central to precision nutrition responses may be most precisely quantified via whole room indirect calorimetry over 24-h, in which precise control of activity and nutrition can be achieved. In addition, these studies represent unique "N of 1" human crossover metabolic-physiologic experiments during which specific molecular pathways central to nutrient metabolism may be discerned. Here, we quantified 263 circulating metabolites during a ≈40-day inpatient admission in which up to 94 participants underwent seven monitored 24-h nutritional interventions of differing macronutrient composition in a whole-room indirect calorimeter to capture precision metabolic responses. Broadly, we observed heterogenous responses in metabolites across dietary chambers, with the exception of carnitines which tracked with 24-h respiratory quotient. We identified excursions in shared metabolic species (e.g., carnitines, glycerophospholipids, amino acids) that mapped onto gold-standard calorimetric measures of substrate oxidation preference and lipid availability. These findings support a coordinated metabolic-physiologic response to nutrition, highlighting the relevance of these controlled settings to uncover biological pathways of energy utilization during precision nutrition studies.

Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults.

OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.

Twenty-Four-Hour Urinary Sugars Biomarker in a Vending Machine Intake Paradigm in a Diverse Population.

Accurately measuring dietary sugars intake in large-scale epidemiological studies is necessary to understand dietary sugars' true impact on health. Researchers have developed a biomarker that can be used to assess total sugars intake. Our objective is to test this biomarker in diverse populations using an ad libitum intake protocol. Healthy adult participants (n = 63; 58% Indigenous Americans/Alaska Natives; 60% male; BMI (mean ± SD) = 30.6 ± 7.6 kg.m2) were admitted for a 10-day inpatient stay. On day 2, body composition was measured by DXA, and over the last 3 days, ad libitum dietary intake was measured using a validated vending machine paradigm. Over the same days, participants collected daily 24 h urine used to measure sucrose and fructose. The 24 h urinary sucrose and fructose biomarker (24hruSF) (mg/d) represents the sum of 24 h urinary sucrose and fructose excretion levels. The association between the 3-day mean total sugars intake and log 24uSF level was assessed using the Pearson correlation. A linear mixed model regressing log-biomarker on total sugars intake was used to investigate further the association between biomarker, diet, and other covariates. Mean (S.D.) total sugars intake for the group was 197.7 g/d (78.9). Log 24uSF biomarker was moderately correlated with total sugars intake (r = 0.33, p = 0.01). In stratified analyses, the correlation was strongest in females (r = 0.45, p = 0.028), the 18-30 age group (r = 0.44, p = 0.079), Indigenous Americans (r = 0.51, p = 0.0023), and the normal BMI category (r = 0.66, p = 0.027). The model adjusted for sex, age, body fat percent, and race/ethnicity demonstrated a statistically significant association between 24uSF and total sugars intake (ß = 0.0027, p < 0.0001) and explained 31% of 24uSF variance (marginal R2 = 0.31). Our results demonstrated a significant relationship between total sugars intake and the 24uSF biomarker in this diverse population. However, the results were not as strong as those of controlled feeding studies that investigated this biomarker.

Dietary Adherence Is Associated with Perceived Stress, Anhedonia, and Food Insecurity Independent of Adiposity.

We examined whether perceived stress, anhedonia, and food insecurity were associated with dietary adherence during a 6-week intervention. Sixty participants (23 m; 53 ± 14 y) completed psychosocial measures and were provided with full meals. Individuals with obesity were randomized to a weight-maintaining energy needs (WMENs) (n = 18; BMI 33 ± 4) or a 35% calorie-reduced diet (n = 19; BMI 38 ± 9); normal-weight individuals (n = 23; BMI 23 ± 2) were assigned to a WMENs diet. Adherence scores were determined via weekly assessments and daily ecological momentary assessments (EMAs) of real-time behavior in a natural environment. Perceived stress and anhedonia were associated with % body fat (all r-values > 0.25, all p-values < 0.05), but food insecurity and adherence were not. Higher perceived stress (r = -0.31, p = 0.02), anhedonia (r = -0.34, p = 0.01), and food insecurity (r = -0.27, p = 0.04) were associated with lower adherence scores, even after adjusting for age, sex, and % body fat. In all adjusted models, % body fat was not associated with adherence. Higher measures of stress, anhedonia, and food insecurity predicted lower adherence independently of body fat, indicating that psychosocial factors are important targets for successful adherence to dietary interventions, regardless of body size.

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

AIM: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. MATERIALS AND METHODS: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). RESULTS: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). CONCLUSIONS: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.

Emotional Distress Predicts Reduced Type 2 Diabetes Treatment Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%-15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

Impact of Insulin Sensitivity and ß-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy.

OBJECTIVE: To compare the effects of insulin sensitivity and ß-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and ß-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups.

Adipocyte size, adipose tissue calories, and circulating adipokines, before and after diet-induced weight loss in humans.

OBJECTIVE: Adipose tissue (AT) contains a bimodal population of large and small adipocytes. Changes in fat cell size (FCS) distribution and AT caloric density (kcal/g) with weight loss are unclear. We aimed to evaluate changes in FCS and AT calories in weight loss and determine associations with anthropometrics. MATERIALS AND METHODS: Healthy adults (6 men/4 women; age 33 ± 11 years; BMI 35 ± 6 kg/m2) underwent DXA and subcutaneous abdominal/thigh fat biopsies, before and after 6 weeks of caloric restriction. AT calories (bomb calorimetry) and hormones (adiponectin, leptin, FGF21) were measured. RESULTS: Abdominal large cell diameter (LCD; Δ = -13.2 µm, p = 0.01) and nadir (Δ = -7.3 µm, p = 0.03) decreased. In repeated measures correlations (rrm), abdominal and thigh LCD and nadir were associated with fat mass (FM) loss (rrm = 0.68; rrm = 0.63; rrm = 0.66; rrm = 0.62, p's < 0.05, respectively) and waist circumference decrease (rrm = 0.70; rrm = 0.60, p's ≤ 0.05). Small cell percentage did not change and was not associated with FM changes. Abdominal AT calories were unchanged with weight loss. Change in leptin was associated with change in abdominal LCD (rrm = 0.77, p = 0.01). CONCLUSIONS: Caloric restriction reduces adipocyte LCD and nadir. These changes are associated with FM loss. Larger fat cells should be considered as phenotypic targets for weight loss. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov identifier: NCT00687115, May 29, 2008.

Investigation of seasonality of human spontaneous physical activity and energy expenditure in respiratory chamber in Phoenix, Arizona.

OBJECTIVE: The existence of seasonal changes in energy metabolism is uncertain. We investigated the relationship between the seasons and spontaneous physical activity (SPA), energy expenditure (EE), and other components measured in a respiratory chamber. METHODS: Between 1985-2005, 671 healthy adults (aged 28.8 ± 7.1 years; 403 men) in Phoenix, Arizona had a 24-hour stay in the respiratory chamber equipped with radar sensors; SPA (expressed as a percentage over the time interval), the energy cost of SPA, EE, and respiratory exchange ratio (RER) were measured. RESULTS: In models adjusted for known covariates, SPA (%) was lower during summer (7.2 ± 2.9, p = 0.0002), spring (7.5 ± 2.9, p = 0.025), and fall (7.6 ± 3, p = 0.038) compared to winter (8.3 ± 3.5, reference). Conversely, energy cost of SPA (kcal/h/%) was higher during summer (2.18 ± 0.83, p = 0.0008), spring (2.186 ± 0.83, p = 0.017), and fall (2.146 ± 0.75, p = 0.038) compared to winter (2.006 ± 0.76). Protein (292 ± 117 kcal/day, ß = -21.2, p = 0.08) oxidation rates was lower in the summer compared to winter. Carbohydrate and lipid oxidation rates (kcal/day) did not differ across seasons. RER and 24-h EE did not differ by season. CONCLUSION: SPA, representing fidgeting-like behavior in the chamber, demonstrated a winter peak and summer nadir in humans living in a desert climate. These findings indicate that the physiological propensity for movement may be affected by seasonal factors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00340132, NCT00342732.

New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.

Validation of Total Water Intake from the Automated Self-Administered 24-h Recall, 4-d Food Records, and a Food Frequency Questionnaire Using Doubly Labeled Water.

BACKGROUND: Although prior evidence indicates that water intake is important for health, the ability to accurately measure community-dwelling intake is limited. Only a few studies have evaluated self-reported water intake against an objective recovery biomarker. OBJECTIVES: The aim was to compare preformed water intakes (all sources including food) by multiple Automated Self-Administered 24-h recalls (ASA24s), food frequency questionnaires (FFQs), and 4-d food records (4DFRs) against a recovery biomarker, doubly labeled water (DLW), to assess measurement error. METHODS: Over 1 y, 1082 women and men (50%), aged 50 to 74 y, were asked to complete 6 ASA24s, 2 FFQs, 2 unweighted 4DFRs, and an administration of DLW (n = 686). Geometric means of water intake by self-report tools were compared with DLW. Attenuation factors and correlation coefficients between self-reported and the recovery biomarker (DLW) were estimated. RESULTS: Mean water intakes by DLW were 2777 mL/d (interquartile range, 2350 to 3331) in women and 3243 mL/d (interquartile range, 2720 to 3838) in men. Compared with DLW, water intake was underestimated by 18% to 31% on ASA24s and 43% to 44% on 4DFRs. Estimated geometric means from FFQs differed from DLW by -1% to +13%. For a single ASA24, FFQ, and 4DFR, attenuation factors were 0.28, 0.27, and 0.32 and correlation coefficients were 0.46, 0.48, and 0.49, respectively. Repeated use of 6 ASA24s, 2 FFQs, and 2 4DFRs improved attenuation factors to 0.43, 0.32, and 0.39 and correlation coefficients to 0.58, 0.53, and 0.54, respectively. CONCLUSIONS: FFQs may better estimate population means for usual water intake compared with ASA24 and 4DFR. Similar attenuation factors and correlation coefficients across all self-report tools indicate that researchers have 3 feasible options if the goal is understanding intake-disease relationships. The findings are useful for planning future nutrition studies that set policy priorities for populations and to understand the health impact of water. This trial was registered at clinicaltrials.gov as NCT03268577.

Greater anhedonia scores in healthy individuals are associated with less decline in 24-hour energy expenditure with fasting: Evidence for a link between behavioral traits and spendthrift phenotype.

Obesity rates are increasing and affecting mental health. It is important to understand how behavioral traits such as anhedonia are associated with physiologic traits that may predict weight-change in clinical and non-clinical populations. We studied whether 24-hour energy expenditure (24hEE) changes with fasting and overfeeding are associated with anhedonia in a healthy cohort. We performed behavioral assessments (physical anhedonia scale (PAS) and inventory for depressive symptoms (IDS)) followed by measures of 24hEE and urinary catecholamines in a whole-room indirect calorimeter (respiratory chamber) during energy balance, and then randomly during fasting and 2 different overfeeding diets. Participants (n=98) were medically healthy, between 18 and 55 years of age, with normal glucose regulation and weight-stable 6 months before admission. Women were premenopausal and not pregnant. Higher PAS was significantly associated with lesser decrease in 24hEE with fasting and higher urinary catecholamine excretion rates - consistent with spendthrift metabolism. As IDS increased, the association between anhedonia and the change in 24hEE from energy balance to fasting decreased (B-values were lower for change in EE). Here, higher PAS scores may reflect the ability to respond with appropriate homeostatic reactions which balance energy needs. IDS scores blunting this response may explain how anhedonia and depression can lead to weight gain.

Reproducibility and determinants of the metabolic responses during a mixed-meal tolerance test.

OBJECTIVE: The aim of this study was to assess the reproducibility and physiological determinants of mixed-meal tolerance tests (MMTTs) on glucose and insulin responses. METHODS: While inpatients on a weight-maintaining diet, 894 individuals (574 with normal and 267 with impaired glucose regulation and 53 with type 2 diabetes [T2D]) underwent 9-hour MMTTs (breakfast and lunch; 30% weight-maintaining diet each; 40% carbohydrate, 40% fat, and 20% protein). Total/incremental areas under the curve (AUC/iAUC) were calculated from MMTT plasma glucose/insulin concentrations. Acute insulin response (AIR) was quantified by intravenous glucose tolerance test and insulin action (M) via hyperinsulinemic-euglycemic clamp. A subset had repeat MMTTs (median follow-up = 1.4 years). RESULTS: In individuals without T2D, for breakfast-versus-lunch reproducibility of glucose, AUCs were moderate (intraclass correlation coefficients [ICCs]: 0.44-0.61), and iAUCs were poor (ICCs < 0.15). For repeated MMTTs, reproducibility of AUC/iAUCs was low (ICCs: 0.11-0.36). For insulin, AUC reproducibility was high (ICCs > 0.70), and iAUCs were moderate (ICCs: 0.64-0.71). For repeated MMTTs, ICC AUC/iAUCs were 0.34 to 0.54. In those with T2D, ICC glucose AUC/iAUCs were >0.80 and >0.50, respectively, and for insulin were <0.40. For repeated MMTTs, ICC glucose/insulin AUC/iAUCs were moderate. Glucose AUCs associated with M/AIR (partial Rs < -0.25), and insulin AUCs negatively/positively associated with M/AIR (partial Rs = -0.51/0.24). CONCLUSIONS: Reproducibility of glucose/insulin responses to MMTTs varied by subtraction of fasting values, glucose status, and time. Insulin secretion and action explained ~20% of MMTT responses. The substantial variability in MMTT response requires consideration in studies using MMTT outcomes.

Closed-loop control of air supply to whole-room indirect calorimeters to improve accuracy and standardize measurements during 24-hour dynamic metabolic studies.

OBJECTIVE: The aim of this study was to test proportional-integral-derivative (PID) control of air inflow rate in a whole-room indirect calorimeter to improve accuracy in measuring oxygen (O2 ) consumption ( V ̇ O 2 ) and carbon dioxide (CO2 ) production ( V ̇ CO 2 ). METHODS: A precision gas blender infused nitrogen (N2 ) and CO2 into the calorimeter over 24 hours based on static and dynamic infusion profiles mimicking V ̇ O 2 and V ̇ CO 2 patterns during resting and non-resting conditions. Constant (60 L/min) versus time-variant flow set by a PID controller based on the CO2 concentration was compared based on errors between measured versus expected values for V ̇ O 2 , V ̇ CO 2 , respiratory exchange ratio, and metabolic rate. RESULTS: Compared with constant inflow, the PID controller allowed both a faster rise time and long-term maintenance of a stable CO2 concentration inside the calorimeter, resulting in more accurate V ̇ CO 2 estimates (mean hourly error, PID: -0.9%, 60 L/min = -2.3%, p < 0.05) during static infusions. During dynamic infusions mimicking exercise sessions, the PID controller achieved smaller errors for V ̇ CO 2 (mean: -0.6% vs. -2.7%, p = 0.02) and respiratory exchange ratio (mean: 0.5% vs. -3.1%, p = 0.02) compared with constant inflow conditions, with similar V ̇ O 2 (p = 0.97) and metabolic rate (p = 0.76) errors. CONCLUSIONS: PID control in a whole-room indirect calorimeter system leads to more accurate measurements of substrate oxidation during dynamic metabolic studies.

The association between gut hormones and diet-induced metabolic flexibility in metabolically healthy adults.

OBJECTIVE: This study investigated whether interindividual variance in diet-induced metabolic flexibility is explained by differences in gut hormone concentrations. METHODS: A total of 69 healthy volunteers with normal glucose regulation underwent 24-hour assessments of respiratory quotient (RQ) in a whole-room indirect calorimeter during eucaloric feeding (EBL; 50% carbohydrate, 30% fat) and then, in a crossover design, during 24-hour fasting and three normal-protein (20%) overfeeding diets (200% energy requirements). Metabolic flexibility was defined as the change in 24-hour RQ from EBL during standard (50% carbohydrate), high-fat (60%), and high-carbohydrate (75%) overfeeding diets. Plasma concentrations of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) after an overnight fast were measured prior to and after each diet. RESULTS: Compared with EBL, on average, 24-hour RQ decreased by ~4% during high-fat overfeeding, whereas it increased by ~4% during standard overfeeding and by ~9% during high-carbohydrate overfeeding. During high-carbohydrate overfeeding, but not during any other overfeeding diet or fasting, increased GLP-1 concentration was associated with increased RQ (r = 0.44, p < 0.001), higher/lower carbohydrate/lipid oxidation rates (r = 0.34 and r = -0.51, both p < 0.01), respectively, and increased plasma insulin concentration (r = 0.38, p = 0.02). CONCLUSIONS: Increased GLP-1 concentration following high-carbohydrate overfeeding associated with a greater shift to carbohydrate oxidation, suggesting that GLP-1 may be implicated in diet-induced metabolic flexibility to carbohydrate overload.

Carbon Isotope Ratios of Plasma and RBC Fatty Acids Identify Meat Consumers in a 12-Week Inpatient Feeding Study of 32 Men.

BACKGROUND: Molecular stable isotope ratios are a novel type of dietary biomarker with high sensitivity and specificity for certain foods. Among these, fatty acid carbon isotope ratios (CIRs) have strong potential but have not been investigated as dietary biomarkers. OBJECTIVES: We evaluated whether fatty acid CIRs and mass proportions were associated with meat, fish, and sugar-sweetened beverage (SSB) intake. METHODS: Thirty-two men [aged 46.2 ± 10.5 y; BMI (kg/m2): 27.2 ± 4.0] underwent a 12-wk inpatient dietary intervention at the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Arizona. Men were randomly assigned to 1 of 8 dietary treatments varying the presence/absence of dietary meat, fish, and SSBs in all combinations. Fatty acid CIRs and mass proportions were measured in fasting blood samples and adipose tissue biopsies that were collected pre- and postintervention. Dietary effects were analyzed using multivariable regression and receiver operating characteristic AUCs were calculated using logistic regression. RESULTS: CIRs of the several abundant SFAs, MUFAs and arachidonic acid (20:4n-6) in plasma were strongly associated with meat, as were a subset of these fatty acids in RBCs. Effect sizes in plasma ranged from 1.01‰ to 1.93‰ and were similar but attenuated in RBCs. Mass proportions of those fatty acids were not associated with diet. CIRs of plasma dihomo-γ-linolenic acid (20:3n-6) and adipose palmitic acid (16:0) were weakly associated with SSBs. Mass proportions of plasma odd-chain fatty acids were associated with meat, and mass proportions of plasma EPA and DHA (20:5n-3 and 22:6n-3) were associated with fish. CONCLUSIONS: CIRs of plasma and RBC fatty acids show promise as sensitive and specific measures of dietary meat. These provide different information from that provided by fatty acid mass proportions, and are informative where mass proportion is not. This trial is registered at www.clinicaltrials.gov as NCT01237093.

Disinhibition augments thirst perception from two dehydrating stimuli in men.

Physiological systems controlling water and energy ingestion are coordinated. Whether maladaptive eating behavior and appetite for water are linked is unknown. Thus, we sought to investigate the association between maladaptive eating and both thirst and water drinking behavior with two dehydrating conditions. Twenty-two lean men and 20 men with obesity (mean age 32.3 ± 8.4 years and 30.0 ± 11.1 years, respectively) completed the Three-Factor Eating Questionnaire (TFEQ) and Gormally Binge Eating Scale. On separate days, volunteers were dehydrated by a 2-h hypertonic saline infusion and a 24-h water deprivation, and thirst was measured on a 100-mm visual analogue scale (VAS) during each procedure. After each dehydrating condition, ad libitum water intake was measured. In the saline infusion, higher Disinhibition on the TFEQ was associated with thirst in the lean group (ß = 4.2 mm VAS, p = 0.03) but not in the group with obesity (p = 0.51). In the water-deprivation condition, higher Disinhibition was also associated with thirst in the lean group (ß = 5.6 mm VAS, p = 0.01) with the strength of relationship being 3.5-fold stronger than that observed in the group with obesity (ß = 1.6 mm VAS, p = 0.0003). Hunger, Restraint, and binge-eating scores were not associated with thirst in either dehydrating condition (all p > 0.05). Maladaptive eating behaviors were not associated with ad libitum water intake (all p > 0.05). Disinhibition is associated with higher thirst perception in healthy weight individuals and may be attenuated in obesity. The characteristics of disinhibition which typically includes a heightened readiness to eat, may reflect a more general phenotype that also reflects a readiness to drink.

Improved food Go/No-Go scores after transcranial direct current stimulation (tDCS) to prefrontal cortex in a randomized trial.

OBJECTIVE: Reduced dorsolateral prefrontal cortex (dlPFC) activity and inhibitory control may contribute to obesity. The study objective was to assess effects of repeated transcranial direct current stimulation (tDCS) on food Go/No-Go (GNG), food Stroop performance, and snack food intake. METHODS: Twenty-nine individuals with obesity (12 male; mean [SD], age 42 [11] years; BMI 39 [8]) participated in a combined inpatient/outpatient randomized parallel-design trial and received 15 sessions of anodal or sham tDCS to the left dlPFC. Food-related inhibitory control (GNG), attentional bias (Stroop), and snack food intake were assessed at baseline, completion of inpatient sessions (day 7), and follow-up (day 31). RESULTS: GNG performance improved in the anodal group by day 31, compared with sham (p = 0.01), but Stroop scores did not differ by intervention. Greater snack food intake was associated with lower GNG scores (p = 0.01), driven by the sham group (p < 0.001) and higher food and palatable bias scores on the Stroop (all p = 0.02) across both groups. Changes on tasks were not associated with changes in intake. CONCLUSIONS: Anodal tDCS to the left dlPFC improved performance on a food-related inhibitory control task, providing evidence of potential for therapeutic benefit of neuromodulation in areas controlling executive function. Results showed that tDCS to the dlPFC reduced snack food intake and hunger; however, underlying neurocognitive mechanisms remain uncertain.