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Abstract: Background : Trauma and blood loss are frequently associated with organ failure, immune dysfunction, and a high risk of secondary bacterial lung infections. We aim to test if plasma metabolomic flux and monocyte bioenergetics are altered in association with trauma and related secondary infections. Methods : Plasma samples were collected from trauma patients at three time points: days 0, 3, and 7 postadmission. Metabolites (140) were measured in plasma from trauma survivors ( n = 24) and healthy control individuals (HC, n = 10). Further analysis within the trauma cohort included subsets of trauma/infection-negative (TIneg, n = 12) and trauma/infection-positive patients (TIpos, n = 12). The bioenergetic profile in monocytes was determined using mitochondrial and glycolytic stress tests. Results : In the trauma cohort, significant alterations were observed in 29 metabolites directly affecting 11 major metabolic pathways, while 34 metabolite alterations affected 8 pathways in 9, versus TIneg patients. The most altered metabolic pathways included protein synthesis, the urea cycle/arginine metabolism, phenylalanine, tyrosine, tryptophan biosynthesis, and carnitine compound family. In monocytes from trauma patients, reduced mitochondrial indices and loss of glycolytic plasticity were consistent with an altered profile of plasma metabolites in the tricarboxylic acid cycle and glycolysis. Conclusions : Our study highlights that the metabolic profile is significantly and persistently affected by trauma and related infections. Among trauma survivors, metabolic alterations in plasma were associated with reduced monocyte bioenergetics. These exploratory findings establish a groundwork for future clinical studies aimed at enhancing our understanding of the interplay between metabolic/bioenergetic alterations associated with trauma and secondary bacterial infections., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Background/objectives: Type 1 diabetes (T1D) is associated with an increase in resting metabolic rate (RMR), but the impact of T1D on other components of 24-h energy expenditure (24-h EE) is not known. Also, there is a lack of equations to estimate 24-h EE in patients with T1D. The aims of this analysis were to compare 24-h EE and its components in young adults with T1D and healthy controls across the spectrum of body mass index (BMI) and derive T1D-specific equations from clinical variables., Subjects/methods: Thirty-three young adults with T1D diagnosed ≥1 year prior and 33 healthy controls matched for sex, age and BMI were included in this analysis. We measured 24-h EE inside a whole room indirect calorimeter (WRIC) and body composition with dual x-ray absorptiometry., Results: Participants with T1D had significantly higher 24-h EE than healthy controls (T1D = 2047 ± 23 kcal/day vs control= 1908 ± 23 kcal/day; P < 0.01). We derived equations to estimate 24-h EE with both body composition (fat free mass + fat mass) and anthropometric (weight + height) models, which provided high coefficients of determination (R 2  = 0.912 for both). A clinical model that did not incorporate spontaneous physical activity yielded high coefficients of determination as well (R 2  = 0.897 and R 2  = 0.880 for body composition and anthropometric models, respectively)., Conclusion: These results confirm that young adults with established T1D have increased 24-h EE relative to controls without T1D. The derived equations from clinically available variables can assist clinicians with energy prescriptions for weight management in patients with T1D., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We describe the technology and validation of a new whole room indirect calorimeter (WRIC) methodology to quantify volume of methane (VCH 4 ) released from the human body over 24 h concurrently with the assessment of energy expenditure and substrate utilization. The new system extends the assessment of energy metabolism by adding CH 4 , a downstream product of microbiome fermentation that could contribute to energy balance. Our new system consists of an established WRIC combined with the addition of off-axis integrated-cavity output spectroscopy (OA-ICOS) to measure CH 4 concentration ([CH 4 ]). Development, validation, and reliability of the system included environmental experiments to measure the stability of the atmospheric [CH 4 ], infusing CH 4 into the WRIC and human cross-validation studies comparing [CH 4 ] quantified by OA-ICOS and mid-infrared dual-comb spectroscopy (MIR DCS).Our infusion data indicated that the system measured 24-h [CH 4 ] and VCH 4 with high sensitivity, reliability, and validity. Cross-validation studies showed good agreement between OA-ICOS and MIR DCS technologies (r = 0.979, P < 0.0001). Human data revealed 24-h VCH 4 was highly variable between subjects and within/between days. Finally, our method to quantify VCH 4 released by breath or colon suggested that over 50% of the CH 4 was eliminated through the breath. The method allows, for the first time, measurement of 24-h VCH 4 (in kcal) and therefore the measurement of the proportion of human energy intake fermented to CH 4 by the gut microbiome and released via breath or from the intestine; also, it allows us to track the effects of dietary, probiotic, bacterial, and fecal microbiota transplantation on VCH 4 . NEW & NOTEWORTHY This is the first time that continuous assessment of CH 4 is reported in parallel with measurements of O 2 consumption and CO 2 production inside a whole room indirect calorimeter in humans and over 24 h. We provide a detailed description of the whole system and its parts. We carried out studies of reliability and validity of the whole system and its parts. CH 4 is released in humans during daily activities.

Objective: This analysis aimed to measure the intraparticipant reliability-the intraclass correlation coefficient-of all the components of daily energy expenditure (EE) (24-hour EE, sleep EE, resting EE, basal EE, and thermic effect of food) over a period of 3 consecutive days in 35 study participants., Methods: The components of daily EE and substrate use (respiratory exchange ratio) were measured over 3 consecutive days before and after a 3-week 1,000-kcal/d caloric restriction/weight-loss intervention., Results: There was a high degree of reliability for sleep EE (96.8%), 24-hour EE (97.8%), basal EE (90.6%), and resting EE (93.2%) during the run-in period. The intraclass correlation coefficient for the follow-up period after weight loss (3.67 ± 1.10 kg) remained high for sleep EE (95.6%), 24-hour EE (100%), basal EE (96.1%), and resting EE (92.5%). The minimal detectable differences in EE were reduced by 30% for both 24-hour EE and sleep EE when comparing 2 days versus 1 day spent in the whole-room indirect calorimeter., Conclusions: The reliability of the daily components of EE is very high both prior to and after a weight-loss intervention. We here provide instrumental data for investigators to adequately power studies investigating energy metabolism using whole-room indirect calorimetry., (© 2021 The Obesity Society.)

Background: Low-calorie diet (LCD)-induced weight loss demonstrates response heterogeneity. Physiologically, a decrease in energy expenditure lower than what is predicted based on body composition (metabolic adaptation) and/or an impaired capacity to increase fat oxidation may hinder weight loss. Understanding the metabolic components that characterize weight loss success is important for optimizing weight loss strategies., Objectives: We tested the hypothesis that overweight/obese individuals who had lower than expected weight loss in response to a 28-d LCD would be characterized by 1) impaired fat oxidation and 2) whole-body metabolic adaptation. We also characterized the molecular mechanisms associated with weight loss success/failure., Methods: This was a retrospective comparison of participants who met their predicted weight loss targets [overweight/obese diet sensitive (ODS), n = 23, females = 21, males = 2] and those that did not [overweight/obese diet resistant (ODR), n = 14, females = 12, males = 2] after a 28-d LCD (900-1000 kcal/d). We used whole-body (energy expenditure and fat oxidation) and tissue-specific measurements (metabolic proteins in skeletal muscle, gene expression in adipose tissue, and metabolites in serum) to detect metabolic properties and biomarkers associated with weight loss success., Results: The ODR group had greater mean ± SD metabolic adaptation (-175 ± 149 kcal/d; +119%) than the ODS group (-80 ± 108 kcal/d) after the LCD (P = 0.030). Mean ± SD fat oxidation increased similarly for both groups from baseline (0.0701 ± 0.0206 g/min) to day 28 (0.0869 ± 0.0269 g/min; P < 0.001). A principal component analysis factor comprised of serum 3-hydroxybutyric acid, citrate, leucine/isoleucine, acetyl-carnitine, and 3-hydroxylbutyrlcarnitine was associated with weight loss success at day 28 (std. β = 0.674, R2 = 0.479, P < 0.001)., Conclusions: Individuals who achieved predicted weight loss targets after a 28-d LCD were characterized by reduced metabolic adaptation. Accumulation of metabolites associated with acetyl-CoA excess and enhanced ketogenesis was identified in the ODS group.This trial was registered at clinicaltrials.gov as NCT01616082., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: The aim of this study was to determine the effects of prolonged (72 hours) glucagon administration at a low dose (LD) (12.5 ng/kg/min) and high dose (HD) (25 ng/kg/min) on energy expenditure (EE) in healthy individuals with overweight or obesity., Methods: Thirty-one healthy participants with overweight or obesity (BMI of 27-45 kg/m 2 , 26-55 years old, 23 females) were randomized into LD, HD, or placebo groups and underwent 72-hour intravenous infusion of glucagon. Whole-room calorimetry was used to assess EE and substrate use during five overnight stays (2 days at baseline, 3 days of infusion) and during two 24-hour stays (baseline vs. day 3). Blood was sampled at regular intervals throughout the inpatient stay and analyzed for glucagon and biomarkers of metabolism., Results: HD infusion elevated plasma glucagon levels compared with the placebo and LD infusion (P < 0.001). Sleeping, basal, and 24-hour EE was not significantly different among groups at any time point. Those receiving HD had significantly higher basal fat oxidation (Fat Ox) at days 2 and 3 than those receiving the placebo (P < 0.05); however, no differences in 24-hour Fat Ox were observed among groups (baseline vs. day 3)., Conclusions: An HD plasma glucagon infusion over 72 hours does not increase any aspects of EE in healthy individuals with overweight or obesity., (© 2021 The Obesity Society.)

Background: Human and microbial metabolism are distinct disciplines. Terminology, metrics, and methodologies have been developed separately. Therefore, combining the 2 fields to study energetic processes simultaneously is difficult., Objectives: When developing a mechanistic framework describing gut microbiome and human metabolism interactions, energy values of food and digestive materials that use consistent and compatible metrics are required. As an initial step toward this goal, we developed and validated a model to convert between chemical oxygen demand (COD) and gross energy (${E&#95;g}$) for >100 food items and ingredients., Methods: We developed linear regression models to relate (and be able to convert between) theoretical gross energy (${E&#95;g}^{\prime}$) and chemical oxygen demand (COD'); the latter is a measure of electron equivalents in the food's carbon. We developed an overall regression model for the food items as a whole and separate regression models for the carbohydrate, protein, and fat components. The models were validated using a sample set of computed ${E&#95;g}^{\prime}$ and COD' values, an experimental sample set using measured ${E&#95;g}$ and COD values, and robust statistical methods., Results: The overall linear regression model and the carbohydrate, protein, and fat regression models accurately converted between COD and ${E&#95;g}$, and the component models had smaller error. Because the ratios of COD per gram dry weight were greatest for fats and smallest for carbohydrates, foods with a high fat content also had higher ${E&#95;g}$ values in terms of kcal · g dry weight-1., Conclusion: Our models make it possible to analyze human and microbial energetic processes in concert using a single unit of measure, which fills an important need in the food-nutrition-metabolism-microbiome field. In addition, measuring COD and using the regressions to calculate ${E&#95;g}$ can be used instead of measuring ${E&#95;g}$ directly using bomb calorimetry, which saves time and money., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: A metabolic adaptation, defined as an increase in energy expenditure (EE) beyond what is expected with weight gain during overfeeding (OF), has been reported but also refuted. Much of the inconsistency stems from the difficulty in conducting large, well-controlled OF studies in humans., Objectives: The primary aim of this study was to determine whether a metabolic adaptation to OF exists and if so, attenuates weight gain., Methods: Thirty-five young adults consumed 40% above their baseline energy requirements for 8 wk, and sleeping metabolic rate (SMR) and 24-h sedentary energy expenditure (24h-EE) were measured before and after OF. Subjects were asked to return for a 6-mo post-OF follow-up visit to measure body weight, body composition, and physical activity., Results: After adjusting for gains in fat-free mass and fat mass, SMR increased by 43 ± 123 kcal/d more than expected (P = 0.05) and 24h-EE by 23 ± 139 kcal/d (P = 0.34), indicating an overall lack of metabolic adaptation during OF despite a wide variability in the response. Among the 30 subjects who returned for the 6-mo follow-up visit, those who had a lower-than-predicted SMR (basal EE) retained more of the fat gained during OF. Likewise, subjects displaying a higher-than-predicted sedentary 24h-EE lost significantly more fat during the 6-mo follow-up., Conclusions: Metabolic adaptation to OF was on average very small but variable between subjects, revealing "thrifty" or "spendthrift" metabolic phenotypes related to body weight loss 6 mo later. This trial was registered at clinicaltrials.gov as NCT01672632., (Copyright © American Society for Nutrition 2019.)

Background: Low-carbohydrate diets have been reported to significantly increase human energy expenditure when measured using doubly labeled water (DLW) but not by respiratory chambers. Although DLW may reveal true physiological differences undetected by respiratory chambers, an alternative possibility is that the expenditure differences resulted from failure to correctly estimate the respiratory quotient (RQ) used in the DLW calculations., Objective: To examine energy expenditure differences between isocaloric diets varying widely in carbohydrate and to quantitatively compare DLW data with respiratory chamber and body composition measurements within an energy balance framework., Design: DLW measurements were obtained during the final 2 wk of month-long baseline (BD; 50% carbohydrate, 35% fat, 15% protein) and isocaloric ketogenic diets (KD; 5% carbohydrate, 80% fat, 15% protein) in 17 men with a BMI of 25-35 kg/m2. Subjects resided 2 d/wk in respiratory chambers to measure energy expenditure (EEchamber). DLW expenditure was calculated using chamber-determined RQ either unadjusted (EEDLW) or adjusted (EEDLWΔRQ) for net energy imbalance using diet-specific coefficients. Accelerometers measured physical activity. Body composition changes were measured by dual-energy X-ray absorptiometry (DXA) which were combined with energy intake measurements to calculate energy expenditure by balance (EEbal)., Results: After transitioning from BD to KD, neither EEchamber nor EEbal were significantly changed (∆EEchamber = 24 ± 30 kcal/d; P = 0.43 and ∆EEbal = -141 ± 118 kcal/d; P = 0.25). Similarly, physical activity (-5.1 ± 4.8%; P = 0.3) and exercise efficiency (-1.6 ± 2.4%; P = 0.52) were not significantly changed. However, EEDLW was 209 ± 83 kcal/d higher during the KD (P = 0.023) but was not significantly increased when adjusted for energy balance (EEDLWΔRQ = 139 ± 89 kcal/d; P = 0.14). After removing 2 outliers whose EEDLW were incompatible with other data, EEDLW was marginally increased during the KD by 126 ± 62 kcal/d (P = 0.063) and EEDLW∆RQ was only 46 ± 65 kcal/d higher (P = 0.49)., Conclusions: DLW calculations failing to account for diet-specific energy imbalance effects on RQ erroneously suggest that low-carbohydrate diets substantially increase energy expenditure. This trial was registered at clinicaltrials.gov as NCT01967563., (Published by Oxford University Press on behalf of the American Society for Nutrition 2019.)

Objective: Overfeeding is a strategy for evaluating the effects of excess energy intake. In this secondary analysis we tested the possibility that different levels of dietary protein might differentially modify the response of fatty acyl-carnitines to overfeeding., Methods: Twenty-three healthy adult men and women were overfed by 40% for 8 weeks while in-patients with diets containing 5% (LPD), 15% (NPD) or 25% (HPD) protein. Plasma fatty acyl-carnitines were measured by gas chromatography/mass spectrometry (GC/MS) at baseline and after 8 weeks of overfeeding. Measurements included: body composition by DXA, energy expenditure by ventilated hood and doubly-labeled water, fat cell size from subcutaneous fat biopsies, and fat distribution by CT scan., Results: Analysis was done on 5 groups of fatty acyl-carnitines identified by principal components analysis and 6 individual short-chain fatty acyl carnitines. Higher protein intake was associated with significantly lower 8 week levels of medium chain fatty acids and C2, C4-OH and C 6:1, but higher values of C3 and C5:1 acyl-carnitines derived from essential amino acids. In contrast energy and fat intake were only weakly related to changes in fatty acyl-carnitines. A decease or smaller rise in 8 week medium chain acyl-carnitines was associated with an increase in sleeping energy expenditure (P = 0.0004), and fat free mass (P < 0.0001) and a decrease in free fatty acid concentrations (FFA) (P = 0.0067). In contrast changes in short-chain fatty acyl-carnitines were related to changes in resting energy expenditure (P = 0.0026), and fat free mass (P = 0.0007), and C4-OH was positively related to FFA (P = 0006)., Conclusion: Protein intake was the major factor influencing changes in fatty acyl carnitines during overfeeding with higher values of most acyl-fatty acids on the low protein diet. The association of dietary protein and fat intake may explain the changes in energy expenditure and metabolic variables resulting in the observed patterns of fatty acyl carnitines., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80-120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years. This metabolic adaptation was accompanied by significantly reduced thyroid axis activity and reactive oxygen species (F2-isoprostane) production. Findings from this 2-year CR trial in healthy, non-obese humans provide new evidence of persistent metabolic slowing accompanied by reduced oxidative stress, which supports the rate of living and oxidative damage theories of mammalian aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Despite successful preclinical testing, 85% of early clinical trials for novel drugs fail. Most futilities originate from molecular mechanisms of the drug(s) tested. It is critically important to develop validated human cell-based model systems in which animal-based research can be translated in order to complement the preclinical in vivo findings prior to implementation of a clinical trial. Obesity is associated with reduced circulating levels of Orexin-A (OX-A) in humans. OX-A increases thermogenesis in rodent brown adipose tissue (AT), yet this phenomenon has not been explored in humans., Methods: We established a cell-based model system of human brown and white adipocytes and tested the effects of OX-A on thermogenesis., Results: Contrary to published in vivo and in vitro reports in rodents, OX-A treatment alone or in combination with an adrenergic stimulus did neither enhance thermogenesis nor its related transcriptional program in a human in vitro model of brown adipocytes or AT explants., Conclusions: Translating preclinical findings in human model systems poses a challenge that must be overcome for the development of effective therapeutic compounds and targets.

Glucagon (GCG) acutely stimulates energy expenditure (EE) and hepatic glucose production (HGP) in humans, but whether these effects persist during hyperglucagonemia of longer duration is unclear. Using a prospective, randomized, single-blind, crossover study design, we therefore measured EE and rates of glucose appearance (glucose RA) during three separate infusion protocols in healthy lean males: A) 10-h overnight GCG infusion (6 ng/[kg × min]) followed by 3-h infusion of GCG, octreotide (OCT), and insulin (INS) for basal replacement; B) overnight saline (SAL) infusion followed by GCG/OCT/INS infusion; and C) overnight SAL infusion followed by SAL/OCT/INS infusion. Sleep EE, measured at 6 to 7 h of the overnight infusion, was increased 65-70 kcal/24 h in A compared with B and C. During the 3-h infusion, mean resting EE remained significantly increased in A versus C by ∼50 kcal/24 h; in B, resting EE increased with a statistical trend but was not significantly greater than in C. Glucose RA increased to comparable levels in A and B. We conclude that in healthy lean males, stimulation of EE and HGP is sustained during hyperglucagonemia of longer duration when insulin secretion is inhibited. The increase in EE at the present GCG dose was of marginal clinical significance., (© 2017 by the American Diabetes Association.)

Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.

Context: The effects of caloric restriction (CR) on in vivo muscle mitochondrial function in humans are controversial., Objective: We evaluated muscle mitochondrial function and associated transcriptional profiles in nonobese humans after 12 months of CR., Design: Individuals from an ancillary study of the CALERIE 2 randomized controlled trial were assessed at baseline and 12 months after a 25% CR or ad libitum (control) diet., Setting: The study was performed at Pennington Biomedical Research Center in Baton Rouge, LA., Participants: Study participants included 51 (34 female subjects, 25 to 50 years of age) healthy nonobese individuals randomized to 1 of 2 groups (CR or control)., Intervention: This study included 12 months of a 25% CR or ad libitum (control) diet., Main Outcomes: In vivo mitochondrial function [maximal ATP synthesis rate (ATPmax), ATPflux/O2 (P/O)] was determined by 31P-magnetic resonance spectroscopy and optical spectroscopy, and body composition was determined by dual-energy X-ray absorptiometry. In a subset of individuals, a muscle biopsy was performed for transcriptional profiling via quantitative reverse transcription polymerase chain reaction and microarrays., Results: Weight, body mass index (BMI), fat, and fat-free mass (P < 0.001 for all) significantly decreased at month 12 after CR vs control. In vivo ATPmax and P/O were unaffected by 12 months of CR. Targeted transcriptional profiling showed no effects on pathways involved in mitochondrial biogenesis, function, or oxidative stress. A subgroup analysis according to baseline P/O demonstrated that a higher (vs lower) P/O was associated with notable improvements in ATPmax and P/O after CR., Conclusions: In healthy nonobese humans, CR has no effect on muscle mitochondrial function; however, having a "more coupled" (versus "less coupled") phenotype enables CR-induced improvements in muscle mitochondrial function., (Copyright © 2017 by the Endocrine Society)

Background: The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat., Objective: We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition., Design: Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW)., Results: Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass., Conclusion: The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at clinicaltrials.gov as NCT01967563., (© 2016 American Society for Nutrition.)

Objective: Determine whether prolonged consumption of high- or low-protein diets modifies the thermogenic response to a standard meal., Methods: Twenty-four healthy individuals were randomized to overfeeding diets containing low (5%, n = 8), normal (15%, n = 9), or high (25%, n = 7) protein for 56 days while inpatients. The thermic effect of food (TEF) was measured over 4 h by indirect calorimetry following a standard meal (20% of energy, 20% protein) or a meal that matched the study diet ("study meal")., Results: As expected, the TEF following the study meal (i.e., either low, normal, or high protein content) was significantly associated with dietary protein (P = 0.007), and the TEF was significantly increased in the high-protein diet (15.4%) versus the normal-protein (5.6%) and low-protein diets (6.4%) (P = 0.05 and P = 0.03, respectively). However, returning to a standard meal (20% protein) after 42 days of overfeeding the study diets, the TEF response did not differ from baseline between groups or within subjects regardless of the prolonged intake of the habitual study diet (high protein: P = 0.32, low protein: P = 0.11, normal protein: P = 0.79)., Conclusions: TEF is related to acute dietary protein intake but not altered by prolonged intake of high-energy diets with high or low protein content., (© 2016 The Obesity Society.)

Context: Obesity is associated with insulin resistance and other metabolic changes that might be modified by overfeeding diets with different protein levels., Objective: The objective of the study was to determine the effect of overfeeding diets with 5%, 15%, or 25% energy from protein on insulin sensitivity and compartments of body fat in healthy men and women., Methods: Fifteen men and five women were overfed by approximately 40% for 56 days with 5% (low protein), 15% (normal protein), or 25% (high protein) protein diets. Insulin sensitivity was measured using a two-step insulin clamp at baseline and at 8 weeks. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and multislice computed tomography scan and abdominal sc fat cell size was determined on osmium-fixed fat cells., Setting: This was an in-patient metabolic ward study., Main Outcome Measures: Insulin sensitivity and free fatty acids during low and high levels of insulin infusion before and after 8 weeks after overfeeding and changes in body fat distribution from computed tomography were measured., Results: Total body fat mass, fat-free mass (FFM), visceral adipose tissue (VAT), and deep sc fat all increased with overfeeding. FFM and intrahepatic lipid increased more on the high protein diet, whereas percentage BF and fasting free fatty acids (FFAs) increased more on the low protein diet. Baseline fat cell size predicted the increase in VAT and the magnitude of FFA suppression during the high-dose insulin clamp. Acute release of insulin at baseline predicted the increase in deep sc fat but not VAT. Fasting insulin and glucose increased with overfeeding, but glucose disposal as measured by the clamp was not changed. Suppression of FFAs was less complete during the high-dose insulin infusion after overfeeding., Conclusion: Eight weeks of overfeeding, which increased fat mass including expansion of visceral and deep sc tissues and intrahepatic lipid, increased fasting insulin and glucose, impaired the suppression of FFA but did not produce whole-body insulin resistance.

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35.6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.

Background: Energy expenditure (EE) increases with overfeeding, but it is unclear how rapidly this is related to changes in body composition, increased body weight, or diet., Objective: The objective was to quantify the effects of excess energy from fat or protein on energy expenditure of men and women living in a metabolic chamber., Design: We conducted a randomized controlled trial in 25 participants who ate ∼40% excess energy for 56 d from 5%, 15%, or 25% protein diets. Twenty-four-hour EE (24EE) and sleeping EE (SleepEE) were measured on days 1, 14, and 56 of overfeeding and on day 57 while consuming the baseline diet (usually day 57). Metabolic and molecular markers of muscle metabolism were measured in skeletal muscle biopsy specimens., Results: In the low-protein diet group whose excess energy was fat, the 24EE and SleepEE did not increase during the first day of overfeeding. When extra energy contained protein, both 24EE and SleepEE increased in relation to protein intake (r = 0.50, P = 0.02). The 24EE over 8 wk in all 3 groups was correlated with protein intake (r = 0.60, P = 0.004) but not energy intake (r = 0.16; P = 0.70). SleepEE was unchanged by overfeeding in the low-protein diet group, and baseline surface area predicted increased 24EE in this group. Protein and fat oxidation were reciprocally related during overfeeding. Observed 24EE was higher than predicted on days 1 (P ≤ 0.05), 14 (P = 0.0001), and 56 (P = 0.0007). There was no relation between change in fat mass and change in EE., Conclusions: Excess energy, as fat, does not acutely increase 24EE, which rises slowly as body weight increases. Excess energy as protein acutely stimulates 24EE and SleepEE. The strongest relation with change in 24EE was the change in energy expenditure in tissue other than muscle or fat-free mass., (© 2015 American Society for Nutrition.)

Background: Achieving energy balance is critical for the interpretation of results obtained in respiratory chambers. However, 24-h energy expenditure (24EE) predictions based on estimated resting metabolic rate and physical activity level are often inaccurate and imprecise., Objective: We aimed to develop and validate equations to better achieve energy balance in a respiratory chamber by adding or subtracting food items., Design: By using a randomized data set with measures of 24EE (n = 241) performed at the Pennington Biomedical Research Center, we developed equations to predict 24EE from anthropometric, demographic, and body composition variables before and at 3 and 7 h into the chamber measurement. The equations were tested on an independent data set (n = 240) and compared with published predictive equations., Results: By using anthropometric and demographic variables, the equation was as follows: 24EE (kcal/d) = 11.6 [weight (kg)] + 8.03 [height (cm)] - 3.45 [age (y)] + 217 (male) - 52 (African American) - 235. The mean prediction error was -9 ± 155 kcal/d (2046 ± 305 compared with 2055 ± 343 kcal/d for measured 24EE; P = 0.36). The prediction achieved a precision of ±10% of measured 24EE in 83% of the participants. Energy prescription was then refined by equations with the use of energy expenditure values after 3 h, 7 h, or both into the chamber study. These later equations improved the precision (±10% of measured 24EE) to 92% (P = 0.003) and 96% (P < 0.0001) of the participants at 3 and 7 h, respectively. Body composition did not improve 24EE predictions., Conclusions: We showed the use of a set of equations to prescribe and adjust energy intake to achieve energy balance in respiratory chambers over 24 h. These equations may be used in most respiratory chambers and modified to accommodate exercise or specific feeding protocols.

The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (-77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-δ (PPARδ) by lipolysis products. Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.

Background: Weight loss reduces energy expenditure, but the contribution of different macronutrients to this change is unclear., Hypothesis: We tested the hypothesis that macronutrient composition of the diet might affect the partitioning of energy expenditure during weight loss., Design: A substudy of 99 participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial had total energy expenditure (TEE) measured by doubly labeled water, and resting energy expenditure (REE) measured by indirect calorimetry at baseline and repeated at 6 months in 89 participants. Participants were randomly assigned to one of four diets with either 15 or 25% protein and 20 or 40% fat., Results: TEE and REE were positively correlated with each other and with fat-free mass and body fat, at baseline and 6 months. The average weight loss of 8.1 ± 0.65 kg (least-square mean ± s.e.) reduced TEE by 120 ± 56  kcal per day and REE by 136 ± 18 kcal per day. A greater weight loss at 6 months was associated with a greater decrease in TEE and REE. Participants eating the high-fat diet (HF) lost significantly more fat-free mass (1.52 ± 0.55 kg) than the low-fat (LF) diet group (P<0.05). Participants eating the LF diet had significantly higher measures of physical activity than the HF group., Conclusion: A greater weight loss was associated with a larger decrease in both TEE and REE. The LF diet was associated with significant changes in fat-free body mass and energy expenditure from physical activity compared with the HF diet.

Context: The role of diet composition in response to overeating and energy dissipation in humans is unclear., Objective: To evaluate the effects of overconsumption of low, normal, and high protein diets on weight gain, energy expenditure, and body composition., Design, Setting, and Participants: A single-blind, randomized controlled trial of 25 US healthy, weight-stable male and female volunteers, aged 18 to 35 years with a body mass index between 19 and 30. The first participant was admitted to the inpatient metabolic unit in June 2005 and the last in October 2007., Intervention: After consuming a weight-stabilizing diet for 13 to 25 days, participants were randomized to diets containing 5% of energy from protein (low protein), 15% (normal protein), or 25% (high protein), which they were overfed during the last 8 weeks of their 10- to 12-week stay in the inpatient metabolic unit. Compared with energy intake during the weight stabilization period, the protein diets provided approximately 40% more energy intake, which corresponds to 954 kcal/d (95% CI, 884-1022 kcal/d)., Main Outcome Measures: Body composition was measured by dual-energy x-ray absorptiometry biweekly, resting energy expenditure was measured weekly by ventilated hood, and total energy expenditure by doubly labeled water prior to the overeating and weight stabilization periods and at weeks 7 to 8., Results: Overeating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88-4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84-7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23-7.79 kg) (P = .002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102-218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165-289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11-3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37-3.98 kg]) increased significantly with the normal and high protein diets., Conclusions: Among persons living in a controlled setting, calories alone account for the increase in fat; protein affected energy expenditure and storage of lean body mass, but not body fat storage., Trial Registration: clinicaltrials.gov Identifier: NCT00565149.

Context: Lorcaserin, a selective 5-hydroxytryptamine (5-HT)(2C) receptor agonist, reduces body weight. It is unclear whether weight loss is due to reduced energy intake (EI) or also to enhanced energy expenditure (EE)., Objective: This study tested the effect of lorcaserin on EI and EE., Design, Participants, and Intervention: In a double-blind, randomized, placebo-controlled trial, 57 (39 women) overweight and obese (body mass index, 27-45 kg/m(2)) adults were randomized to placebo (n = 28) or 10 mg twice daily lorcaserin (n = 29) for 56 d. Weight maintenance was imposed during d 1-7. Beginning on d 8, participants followed a diet and exercise plan targeting a 600 kcal/d deficit., Outcomes: At baseline and after 7 and 56 d of treatment, we measured body weight, body composition (dual x-ray absorptiometry), blood pressure, heart rate, EI at lunch and dinner, subjective appetite ratings, and 24-h EE and 24-h-respiratory quotient (RQ), measured by indirect calorimetry in a respiratory chamber., Results: After 7 d of weight maintenance, EI was significantly (P < 0.01) reduced with lorcaserin but not placebo (mean ± sem for lorcaserin, -286 ± 86 kcal; placebo, -147 ± 89 kcal). After 56 d, lorcaserin resulted in significantly larger reductions in body weight (lorcaserin, -3.8 ± 0.4 kg; placebo, -2.2 ± 0.5 kg; P < 0.01), EI (lorcaserin, -470 ± 87 kcal; placebo, -205 ± 91 kcal; P < .05), and appetite ratings than in placebo. Changes in 24-h EE and 24-h RQ did not differ between groups, even after 24-h EE was adjusted for body weight and composition. Compared with placebo, lorcaserin had no effect on systolic or diastolic blood pressure or heart rate after 56 d., Conclusions: Lorcaserin reduces body weight through reduced EI, not altered EE or RQ.

Objective: A reduction in glycogen after the switch to an isoenergetic high-fat diet (HFD) might promote a compensatory increase in food intake to reestablish carbohydrate balance. We assessed the effect of an isoenergetic switch from a 49%-carbohydrate to 50%-fat diet on nutrient balance and ad libitum food intake. We hypothesized that carbohydrate balance would be inversely related to ad libitum energy intake., Methods: In 47 men and 11 women (22.6+/-0.4 years; 26.1+/-0.5 kg m(-2)), fuel balance was measured in a respiration chamber over 4 days. During the first day, an isoenergetic, high-carbohydrate diet was provided followed by a 3-day isoenergetic, HFD. At the end of this period and after 16 h of fasting, three options of foods (cookies, fruit salad and turkey sandwich) were offered ad libitum for 4 h. The relationships between post-chamber ad libitum intake and macronutrient oxidation and balance measured day-to-day and over the 4-day respiration chamber stay were studied., Results: After switching to a HFD, 24-h respiratory quotient decreased from 0.87+/-0.02 to 0.83+/-0.02 (P<0.0001) resulting in a 4-day cumulative carbohydrate, fat and protein balances of -183+/-368, 342+/-480 and 65+/-267 kcal, respectively. Cumulative energy balance (224+/-362 kcal per 4 days) did not influence ad libitum energy intake. However, we detected that 4-day carbohydrate balance was a positive and independent predictor of post-chamber ad libitum energy intake (R (2)=0.10; P=0.01), whereas no significant influence of fat and protein balances was found., Conclusion: In response to an isoenergetic change from a high-carbohydrate to HFD, higher carbohydrate balance related to increased energy intake.

Objective: This study assessed longitudinal changes in body composition, fat distribution and energy balance in perimenopausal women. We hypothesized that total fat and abdominal body fat would increase at menopause due to decreased energy expenditure (EE) and declining estrogen, respectively., Design: Observational, longitudinal study with annual measurements for 4 years., Subjects: Healthy women (103 Caucasian; 53 African-American), initially premenopausal. During follow-up, lack of menstruation for 1 year and follicle-stimulating hormone >30 mIU ml(-1) defined a subject as postmenopausal., Measurements: Fat and lean mass (dual-energy X-ray absorptiometry), visceral (VAT) and subcutaneous abdominal fat (SAT) (computed tomography), dietary intake (4-day food record), serum sex hormones and physical activity (tri-axial accelerometry). Twenty-four hour EE was measured by whole-room calorimeter in a subset of 34 women at baseline and at year 4., Results: Body fat and weight increased significantly over time only in those women who became postmenopausal by year 4 (n=51). All women gained SAT over time; however, only those who became postmenopausal had a significant increase in VAT. The postmenopausal group also exhibited a significant decrease in serum estradiol. Physical activity decreased significantly 2 years before menopause and remained low. Dietary energy, protein, carbohydrate and fiber intake were significantly higher 3-4 years before the onset of menopause compared with menopause onset. Twenty-four hour EE and sleeping EE decreased significantly with age; however, the decrease in sleeping EE was 1.5-fold greater in women who became postmenopausal compared with premenopausal controls (-7.9 vs -5.3%). Fat oxidation decreased by 32% in women who became postmenopausal (P<0.05), but did not change in those who remained premenopausal., Conclusion: Middle-aged women gained SAT with age, whereas menopause per se was associated with an increase in total body fat and VAT. Menopause onset is associated with decreased EE and fat oxidation that can predispose to obesity if lifestyle changes are not made.

Purpose of Review: This review highlights some recent findings regarding nutritional and endocrine regulators of mitochondrial mass and function and their association with insulin resistance., Recent Findings: Insulin resistance is central to many chronic metabolic diseases, including obesity, type 2 diabetes, dyslipidemia, and hypertension. Insulin resistance in skeletal muscle is associated with lower mitochondrial mass and reduced oxidative phosphorylation. Part of the mitochondrial dysfunction can be triggered by adverse nutrition. Increased fatty acid exposure, resulting from high fats diets or overfeeding, is linked to both decreased mitochondrial number and markers of oxidative phosphorylation. Caloric restriction and the adiponectin signaling pathway, however, can stimulate mitochondrial biogenesis by elevating the transcriptional machinery that regulates mitochondrial mass, improving mitochondrial efficiency, activating the peroxisome proliferator-activated receptor coactivator 1alpha mediated reactive oxygen species scavenging mechanism, and lowering reactive oxygen species production., Summary: States of insulin resistance are characterized by defects in lipid and carbohydrate metabolism. Abnormalities in oxidative capacity, however, can be partially normalized by caloric restriction by modulating mitochondrial mass in an insulin sensitizing manner.

Objective: Our objective was to test the safety and metabolic effects of a novel beta(3)-adrenoreceptor agonist (TAK-677) in humans., Design, Setting, and Participants: Sixty-five obese (body mass index = 33.9 +/- 2.1 kg/m2, mean +/- se) men and women (31.4 +/- 0.9 yr) participated in a double-blind placebo-controlled study at an institutional research center., Intervention: Participants were randomized to 0.1 mg TAK-677 twice daily (BID) (n = 21), 0.5 mg TAK-677 BID (n = 22), or placebo BID (n = 22) for 29 d., Outcomes: Drug safety, 24-h respiratory quotient (RQ), 24-h energy expenditure (EE), body composition, fat distribution, and fasting plasma concentration of substrates and hormones were assessed. An acute-response study was also conducted., Results: The drug was well tolerated by all participants; however, heart rate was elevated (9 +/- 2 beats per minute) with the 0.5-mg BID dose. After 28 d of treatment and when compared with placebo, there was no change in 24-h RQ with either 0.1-mg BID (P = 0.1) or 0.5-mg BID (P = 1.0) doses of TAK-677. However, TAK, 0.5 mg BID, resulted in a small increase in 24-h EE that was significantly different from placebo [change from baseline, 13 +/- 17 (0.5 mg BID) vs.-39 +/- 18 (placebo) kcal/d, P < 0.05]. Changes in weight, fat-free mass, and abdominal fat depots (visceral or sc) were not different between the three groups, nor were changes in fasting insulin, free fatty acid, or glucose concentrations., Conclusion: TAK-677 has no effect on 24-h RQ or fat oxidation but does slightly increase 24-h EE at the highest dose (0.5 mg BID). The acute studies showed large interindividual variability in plasma concentrations of TAK-677 indicating some possible problems with bioavailability and therefore efficacy.

Insulin resistance is associated with impaired skeletal muscle oxidation capacity and reduced mitochondrial number and function. Here, we report that adiponectin signaling regulates mitochondrial bioenergetics in skeletal muscle. Individuals with a family history of type 2 diabetes display skeletal muscle insulin resistance and mitochondrial dysfunction; adiponectin levels strongly correlate with mtDNA content. Knockout of the adiponectin gene in mice is associated with insulin resistance and low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle. Adiponectin treatment of human myotubes in primary culture induces mitochondrial biogenesis, palmitate oxidation, and citrate synthase activity, and reduces the production of reactive oxygen species. The inhibition of adiponectin receptor expression by siRNA, or of AMPK by a pharmacological agent, blunts adiponectin induction of mitochondrial function. Our findings define a skeletal muscle pathway by which adiponectin increases mitochondrial number and function and exerts antidiabetic effects.

Background: Prolonged dietary restriction increases the life span in rodents. Some evidence suggests that alternate-day fasting may also prolong the life span., Objective: Our goal was to determine whether alternate-day fasting is a feasible method of dietary restriction in nonobese humans and whether it improves known biomarkers of longevity., Design: Nonobese subjects (8 men and 8 women) fasted every other day for 22 d. Body weight, body composition, resting metabolic rate (RMR), respiratory quotient (RQ), temperature, fasting serum glucose, insulin, free fatty acids, and ghrelin were assessed at baseline and after 21 d (12-h fast) and 22 d (36-h fast) of alternate-day fasting. Visual analogue scales were used to assess hunger weekly., Results: Subjects lost 2.5 +/- 0.5% of their initial body weight (P < 0.001) and 4 +/- 1% of their initial fat mass (P < 0.001). Hunger increased on the first day of fasting and remained elevated (P < 0.001). RMR and RQ did not change significantly from baseline to day 21, but RQ decreased on day 22 (P < 0.001), which resulted in an average daily increase in fat oxidation of > or =15 g. Glucose and ghrelin did not change significantly from baseline with alternate-day fasting, whereas fasting insulin decreased 57 +/- 4% (P < 0.001)., Conclusions: Alternate-day fasting was feasible in nonobese subjects, and fat oxidation increased. However, hunger on fasting days did not decrease, perhaps indicating the unlikelihood of continuing this diet for extended periods of time. Adding one small meal on a fasting day may make this approach to dietary restriction more acceptable.

Background: Several clinical studies have demonstrated that body weight increases after treatment with thiazolidinediones (TZDs). Prior studies have demonstrated an increase in insulin-stimulated lipid storage in adipose tissue. Some, but not all, studies demonstrate reductions in visceral adipose tissue. Changes in body weight are the result of changes in energy intake, energy expenditure, or both., Objectives: Based on these findings, the primary aim of this study was to evaluate the effect of TZDs on visceral, subcutaneous, and total body fat. Secondary aims were to determine the effects of pioglitazone on (a) energy expenditure, (b) hunger and satiety, (c) blood lipids, and (d) the role of insulinemia/sulfonylurea usage on weight gain in patients with type 2 diabetes., Subjects and Methods: We performed a randomized, double-blind, placebo-controlled trial in 48 men and women with type 2 diabetes who had not previously received treatment with TZDs. Patients were treated for 24 weeks with 45 mg/d of pioglitazone or a matching placebo. Body composition was measured by dual-energy x-ray absorptiometry. Visceral and subcutaneous fat were measured by computed tomography. Resting metabolic rate and thermogenic response to a test meal were measured by indirect calorimetry before and after a standardized meal. Hunger and satiety were measured with visual analog scales before and after the same test meal. Blood was collected for the measurement of fasting glucose and insulin levels, hemoglobin A 1c levels, and lipid content., Results: Pioglitazone treatment resulted in a decrease in hemoglobin A(1c) level by 0.96 +/- 1.1% vs 0.11 +/- 0.8% in the placebo group (P < .005). Body weight and fat increased steadily in the patients treated with pioglitazone during the 6 months of the study (+3.9 +/- 3.1 kg at 6 months in pioglitazone-treated patients vs -0.8 +/- 3.4 kg in the placebo-treated patients). Subcutaneous fat in the trunk, arms, and legs were all increased in the pioglitazone-treated group. Visceral fat did not change significantly in either group. Neither resting metabolic rate nor the thermogenic responses to a meal were altered by pioglitazone. Subjective measures of hunger (visual analog scale) did not change with pioglitazone treatment. Triglycerides fell in the pioglitazone-treated group (-58.5 +/- 124 mg/dL, P < .003). Neither the prior use of sulfonylureas nor the level of insulinemia before treatment was a predictor of weight or fat change., Conclusion: Pioglitazone increased subcutaneous body fat, but not visceral fat. There was no measurable effect on energy expenditure or hunger/satiety. In contrast to the placebo-treated patient with diabetes, weight gain occurs in the face of falling hemoglobin A(1c) and triglyceride levels.

Background: Menopause is a time of increased risk of obesity in women. The effect of menopause in African American women, in whom obesity is already highly prevalent, is unknown., Objective: We compared dietary intakes and energy expenditure (EE) between middle-aged, premenopausal African American and white women participating in a longitudinal study of the menopausal transition., Design: Dietary intakes by food record, EE by triaxial accelerometer, physical activity by self-report, and body composition by dual-energy X-ray absorptiometry were compared in 97 white and 52 African American women. Twenty-four-hour and sleeping EE were measured by whole-room indirect calorimetry in 56 women., Results: Sleeping EE (adjusted for lean and fat mass) was lower in African American than in white women (5749 +/- 155 compared with 6176 +/- 75 kJ/d; P = 0.02); however, there was no significant difference in 24-h EE between groups. Reported leisure activity over the course of a week was less in African American than in white women (556 +/- 155 compared with 1079 +/- 100 kJ/d; P = 0.02), as were the daily hours spent standing and climbing stairs. Dietary intakes of protein, fiber, calcium, magnesium, and several fatty acids were significantly less in African Americans, whereas there were no observed ethnic differences in intakes of fat or carbohydrate. Body fat within the whole group was positively correlated with total, saturated, and monounsaturated fat intakes and inversely associated with fiber and calcium intakes. Fiber was the strongest single predictor of fatness., Conclusion: Ethnic differences in EE and the intake of certain nutrients may influence the effect of menopausal transition on obesity in African American women.

Objectives: In studies that involve the use of a room calorimeter, 24 h energy intake is often larger than 24 h energy expenditure (24 h EE) because of a decrease in activity energy expenditure due to the confined space. This positive energy balance can have large consequences for the interpretation of substrate balances. The objective of this study was to develop a method for predicting an individual's 24 h EE in a room calorimeter at both low (1.4xRMR) and high (1.8xRMR) levels of physical activity., Methods: Two methods are presented that predict an individual's 24 h EE in a metabolic chamber. The first method was based on three components: (1) a 30 min measurement of resting metabolic rate (RMR) using a ventilated hood system; (2) measurement of exercise energy expenditure during 10 min of treadmill walking; and (3) estimation of free-living energy expenditure using a tri-axial motion sensor. Using these measurements we calculated the amount of treadmill time needed for each individual in order to obtain a total 24 h EE at either a low (1.4xRMR) or a high (1.8xRMR) level of physical activity. We also developed a method to predict total 24 h EE during the chamber stay by using the energy expenditure values for the different levels of activity as measured during the hours already spent in the chamber. This would provide us with a tool to adjust the exercise time and/or energy intake during the chamber stay., Results: Method 1: there was no significant difference in expected and measured 24 h EE under either low (9.35+/-0.56 vs 9.51+/-0.47 MJ/day; measured vs predicted) or high activity conditions (13.41+/-0.74 vs 13.97+/-0.78 MJ/day; measured vs predicted). Method 2: the developed algorithm predicted 24 h EE for 97.6+/-4.0% of the final value at 3 h into the test day, and for 98.6+/-3.7% at 7 h into the test day., Conclusion: Both methods provide accurate prediction of energy expenditure in a room calorimeter at both high and low levels of physical activity. It equally shows that it is possible to accurately predict total 24 h EE from energy expenditure values obtained at 3 and 7 h into the study.

CRH increases energy expenditure and decreases food intake in experimental animals. We proposed the hypothesis that peripheral administration of CRH might increase energy expenditure in human subjects. Four men and four women (age, 19-39 yr) were randomized to a double blind, cross-over trial to test the effect of human CRH (hCRH), ovine CRH (oCRH), and placebo on resting energy expenditure measured by indirect calorimetry. CRH was administered by primed continuous infusion at progressively increasing doses of 0.5, 1.0, and 2.0 microg/kg.h at 2-h intervals. hCRH increased resting energy expenditure by 13.9% at the end of the infusion. Respiratory quotient fell from 0.828 to 0.768 during the hCRH infusion compared with a fall from 0.836 to 0.807 during placebo infusion (P < 0.05). Fat oxidation increased by 55% compared with placebo at the highest dose of hCRH. Heart rate increased during hCRH to 10.7 bpm higher than placebo (P < 0.05). oCRH did not increase heart rate. oCRH also had no significant effect on respiratory quotient, and only a small effect on energy expenditure. During hCRH infusion, venous plasma epinephrine, norepinephrine, glycerol, and nonesterified fatty acid levels were not significantly different from those during placebo treatment. Peripheral CRH administration offers a novel strategy to increase energy expenditure.

Although T3 exerts major regulatory actions in both animals and humans, most clinical studies of T3 administration have been relatively short term. The present study examined the effects of more than 2 months (63 days) of low dose T3 treatment on nitrogen balance, body composition, 24-h energy expenditure (EE), and protein turnover in seven healthy men studied at an in-patient metabolic unit. Subjects were also randomly assigned to either high or low fat diets to determine the effects of diet composition. T3 treatment produced significant losses in both lean mass (1.5 +/- 0.3 kg) and fat mass (2.7 +/- 0.4 kg) by 6 weeks, with similar reductions in both at 9 weeks. The high fat diet somewhat attenuated the loss of body fat. Nitrogen balance was significantly negative for the first 3 weeks of T3 treatment, but tended to return to baseline thereafter. There were no significant effects of treatment on protein turnover at 9 weeks, although there was a slight increase in leucine oxidation (P = 0.07). Despite the apparent adaptation in nitrogen balance, total 24-h EE and sleeping EE were significantly increased at 9 weeks. We conclude that although healthy men are able to adapt to mild hyperthyroidism in terms of nitrogen balance, they exhibit significant and persistent changes in fat and fat-free mass as well as energy balance.