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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.

Background:\ud The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 trial tested the effects of two years of 25% calorie restriction (CR) on aging in humans. CALERIE 2 was one of the first studies to use a graph of predicted weight loss to: 1) provide a proxy of dietary adherence, and 2) promote dietary adherence. Assuming 25% CR, each participant's weight over time was predicted, with upper and lower bounds around predicted weights. Thus, the resulting weight graph included a zone or range of body weights that reflected adherence to 25% CR, and this was named the zone of adherence. Participants were considered adherent if their weight was in this zone. It is unlikely, however, that the entire zone reflects 25% CR.\ud \ud Objectives:\ud To determine the level of CR associated with the zone of adherence and if the level of CR achieved by participants was within the zone.\ud \ud Methods:\ud Percent CR associated with the upper and lower bounds of the zone were determined via the Body Weight Planner (https://www.niddk.nih.gov/bwp) for participants in the CALERIE 2 CR group (N = 143). Percent CR achieved by participants was estimated with the intake-balance method.\ud \ud Results:\ud At month 24, the zone of adherence ranged from 10.4(0.0)% to 19.4(0.0)% CR [Mean(SEM)], and participants achieved 11.9(0.7)% CR and were in the zone.\ud \ud Conclusion:\ud The results highlight the challenges of: 1) setting a single CR goal vs. a range of acceptable values, and 2) obtaining real-time and valid measures of CR adherence to facilitate adherence.

Background Type 2 resistant starch (RS2) has been shown to improve metabolic health outcomes and may increase satiety and suppress appetite and food intake in humans. Objective This study assessed whether 12 weeks of daily RS2 supplementation could influence appetite perception, food intake, and appetite-related gut hormones in adults with prediabetes, relative to the control (CTL) group. Design The study was a randomized controlled trial and analysis of secondary study end points. Participants/setting Sixty-eight adults (body mass index ≥27) aged 35 to 75 years with prediabetes were enrolled in the study at Pennington Biomedical Research Center (2012 to 2016). Fifty-nine subjects were included in the analysis. Intervention Participants were randomized to consume 45 g/day of high-amylose maize (RS2) or an isocaloric amount of the rapidly digestible starch amylopectin (CTL) for 12 weeks. Main outcome measures Subjective appetite measures were assessed via visual analogue scale and the Eating Inventory; appetite-related gut hormones (glucagon-like peptide 1, peptide YY, and ghrelin) were measured during a standard mixed-meal test; and energy and macronutrient intake were assessed by a laboratory food intake (buffet) test, the Remote Food Photography Method, and SmartIntake app. Statistical analyses performed Data were analyzed using linear mixed models, adjusting for treatment group and time as fixed effects, with a significance level of α=.05. Results RS2 had no effect on subjective measures of appetite, as assessed by visual analogue scale (P>0.05) and the Eating Inventory (P≥0.24), relative to the CTL group. There were no effects of RS2 supplementation on appetite-related gut hormones, including glucagon-like peptide 1 (P=0.61), peptide YY (P=0.34), and both total (P=0.26) and active (P=0.47) ghrelin compared with the CTL. RS2 had no effect on total energy (P=0.30), carbohydrate (P=0.11), protein (P=0.64), or fat (P=0.37) consumption in response to a buffet meal test, relative to the CTL. In addition, total energy (P=0.40), carbohydrate (P=0.15), protein (P=0.46), and fat (P=0.53) intake, as quantified by the Remote Food Photography Method, were also unaffected by RS2, relative to the CTL. Conclusions RS2 supplementation did not increase satiety or reduce appetite and food intake in adults with prediabetes.

Context This study was designed to understand causes and critical periods for postpartum weight retention by characterizing changes in body composition, energy intake, energy expenditure and physical activity in women with obesity during pregnancy and postpartum. Design In this prospective, observational cohort study, body composition (plethysmography), energy expenditure (doubly labeled water, whole-body room calorimetry), physical activity (accelerometry), metabolic biomarkers, and eating behaviors were measured. Energy intake was calculated by the intake-balance method for pregnancy, and for 2 postpartum periods (0 to 6 months and 6 to 12 months). Results During the 18-month observation period, weight loss occurred in 16 (43%) women (mean ± SEM, −4.9 ± 1.6 kg) and weight retention occurred in 21 (57%) women (+8.6 ± 1.4 kg). Comparing women with postpartum weight loss and weight retention, changes in body weight were not different during pregnancy (6.9 ± 1.0 vs 9.5 ± 0.9 kg, P = 0.06). After pregnancy, women with postpartum weight loss lost −3.6 ± 1.8 kg fat mass whereas women with weight retention gained 6.2 ± 1.7 kg fat mass (P < 0.001). Women with postpartum weight loss reduced energy intake during the postpartum period (compared with during pregnancy) by 300 kcal/d (1255 kJ/d), while women with weight retention increased energy intake by 250 kcal/d (1046 kJ/d, P < 0.005). There were no differences in the duration of breastfeeding, eating behavior, or metabolic biomarkers. Conclusions Postpartum weight gain was the result of increased energy intake after pregnancy rather than decreased energy expenditure. Dietary intake recommendations are needed for women with obesity during the postpartum period, and women should be educated on the risk of overeating after pregnancy.

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight-loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long-lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The db/db mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue. Oral administration of pioglitazone lowered blood glucose levels in db/db mice with a corresponding increase in respiratory quotient, which indicates improved whole-body carbohydrate utilization. In addition, white adipose tissue from db/db mice and from humans treated with pioglitazone showed increased expression of glycerol kinase. Both db/db mice and humans given pioglitazone displayed increased expression of UCP-1, a marker typically associated with brown adipose tissue. Moreover, pancreatic β-cells from db/db mice treated with pioglitazone had greater expression of insulin and Nkx6.1 as well as reduced abundance of the de-differentiation marker Aldh1a3. Collectively, these findings indicate that four weeks of pioglitazone therapy improved overall metabolic health in db/db mice. Our data are consistent with published reports of human subjects administered pioglitazone and with analysis of human adipose tissue taken from subjects treated with pioglitazone. In conclusion, the current study provides evidence that pioglitazone restores key markers of metabolic health and also showcases the utility of the db/db mouse to understand mechanisms associated with human metabolic disease and interventions that provide therapeutic benefit.

Simple Summary Metabolic flexibility describes the ability to adapt to utilization of metabolic fuels such as carbohydrates, lipids, and proteins as they become available. The RNA binding protein HuR controls this flexibility in mouse and human skeletal muscle, but the molecular mechanisms governing this process remain poorly characterized. Additionally, studies from mice indicate that HuR control of metabolic flexibility may be more essential for males than females. This is because males lacking HuR in skeletal muscle develop hallmarks of insulin sensitivity, while females have not been shown to do so. Here we examine this sexual dimorphism in mice lacking HuR in skeletal muscle. Our results reveal that lack of HuR in skeletal muscle drives increased adiposity regardless of sex, but that this increase in adiposity drives the development of insulin resistance in male animals only. Additionally, relative to male mice, the detrimental metabolic phenotype associated with HuR inhibition in skeletal muscle can be corrected by feeding of a diet heavily composed of either lipids or carbohydrates. Abstract Male mice lacking HuR in skeletal muscle (HuRm−/−) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuRm−/− mice. Here we examine this sexually dimorphic phenotype. HuRm−/− mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuRm−/− mice as a driver of decreased glucose clearance. However, HuRm−/− female mice show decreased blood glucose levels during GTT relative to controls. HuRm−/− mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuRm−/− mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuRm−/− male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuRm−/− male mice relative to controls regardless of diet. This pathway is only decreased in female HuRm−/− mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice.

We previously showed that nightly exposure to moderate hypoxia reduces fasting glucose levels and improves both whole-body skeletal muscle and hepatic insulin sensitivity in individuals with obesity. The goal of this study was to extend this observation in an “at home” setting and determine if nightly exposure to moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Eight adults, ages 20–65 years with type 2 diabetes enrolled in our study and slept for 14 consecutive nights at home in a hypoxic tent maintained at 15% O(2) (~2400 m). The primary endpoint was insulin sensitivity (Matsuda Index) calculated from a 75-g oral glucose tolerance test. Secondary endpoints included calculations of insulin secretion and beta-cell function, including the area-under-the-curve (AUC) for glucose and insulin, the Insulinogenic Index, and the Disposition Index. We observed the Matsuda Index trended towards a 29% increase following 14 nights of moderate hypoxia (from 1.7 ± 0.7 to 2.2 ± 1.7; p = 0.06). Two-hour glucose AUC was significantly reduced from 501 ± 99 to 439 ± 65 mg/dL × h (p = 0.01). We conclude that 14 nights of moderate hypoxia improves glucose tolerance in individuals with type 2 diabetes. Future studies should confirm whether exposure to moderate hypoxia consistently improves glucose homeostasis in larger sample sizes.

Objective The objective of this study was to measure changes in glucose, lipid, and inflammation parameters after transitioning from a baseline diet (BD) to an isocaloric ketogenic diet (KD). Methods Glucose homeostasis, lipid homeostasis, and inflammation were studied in 17 men (BMI: 25-35 kg/m2 ) during 4 weeks of a BD (15% protein, 50% carbohydrate, 35% fat) followed by 4 weeks of an isocaloric KD (15% protein, 5% carbohydrate, 80% fat). Postprandial responses were assessed following mixed-meal tests matched to compositions of the BD (control meal [CM]) and KD (ketogenic meal). Results Fasting ketones, glycerol, free fatty acids, glucagon, adiponectin, gastric inhibitory peptide, total and low-density lipoprotein cholesterol, and C-reactive protein were significantly increased on the KD. Fasting insulin, C-peptides, triglycerides, and fibroblast growth factor 21 were significantly decreased. During the KD, the glucose area under the curve was significantly higher with both test meals, and the insulin area under the curve was significantly higher only for the CM. Analyses of glucose homeostasis suggested that the KD insulin sensitivity decreased during the CM but increased during the ketogenic meal. Insulin-mediated antilipolysis was decreased on the KD regardless of meal type. Conclusions Switching to the KD was associated with increased cholesterol and inflammatory markers, decreased triglycerides, and decreased insulin-mediated antilipolysis. Glucose homeostasis parameters were diet dependent and test meal dependent.

Although many individuals achieve weight loss of 10% or more, the ability to maintain a reduced body mass over months and years is much rarer. Unfortunately, our understanding of the adverse consequences of having overweight and obesity argues that long-term maintenance of a reduced weight provides the greatest health benefit. However, to achieve long-term weight reduction requires overcoming neuroendocrine systems that favor restoration of one's initial weight. Identifying and characterizing the components of these systems will be important if we are to develop therapies and strategies to reduce the rates of obesity and its complications in our modern society. During this session, Eric Ravussin and Steven R. Smith, respectively, discussed the physiology of the weight-reduced state that favors weight regain and a molecular component that contributes to this response.

Dynamic phosphorus MRS ((31)P-MRS) is a method used for in vivo studies of skeletal muscle energetics including measurements of phosphocreatine (PCr) resynthesis rate during recovery of submaximal exercise. However, the molecular events associated with the PCr resynthesis rate are still under debate. We assessed vastus lateralis PCr resynthesis rate from (31)P-MRS spectra collected from healthy adults as part of the CALERIE II study (caloric restriction) and assessed associations between PCr resynthesis and muscle mitochondrial signature transcripts and proteins (NAMPT, NQO1, PGC-1α, and SIRT1). Regression analysis indicated that higher concentration of nicotinamide phosphoribosyltransferase (NAMPT) protein, a mitochondrial capacity marker, was associated with faster PCr resynthesis. However, PCr resynthesis was not associated with greater physical fitness (VO(2) peak) or messenger ribonucleic acid levels of mitochondrial function markers such as NQO1, PGC-1α, and SIRT1, suggesting that the impact of these molecular signatures on PCr resynthesis may be minimal in the context of an acute exercise bout. Together, these findings suggest that (31)P-MRS based PCr resynthesis may represent a valid non-invasive surrogate marker of mitochondrial NAMPT in human skeletal muscle.

International audience; This review details the proceedings of a Pennington Biomedical scientific symposium titled, "What Should I Eat and Why? The Environmental, Genetic, and Behavioral Determinants of Food Choice." The symposium was designed to review the literature about energy homeostasis, particularly related to food choice and feeding behaviors, from psychology to physiology. This review discusses the intrinsic determinants of food choice, including biological mechanisms (genetics), peripheral and central signals, brain correlates, and the potential role of the microbiome. This review also address the extrinsic determinants (environment) of food choice within our physical and social environments. Finally, this review reports the current treatment practices for the clinical management of eating-induced overweight and obesity. An improved understanding of these determinants will inform best practices for the clinical treatment and prevention of obesity. Strategies paired with systemic shifts in our public health policies and changes in our "obesogenic" environment will be most effective at attenuating the obesity epidemic.

Whole-room indirect calorimeters have been used to study human metabolism for more than a century. These studies have contributed substantial knowledge to the assessment of nutritional needs and the regulation of energy expenditure and substrate oxidation in humans. However, comparing results from studies conducted at different sites is challenging because of a lack of consistency in reporting technical performance, study design, and results. In May 2019, an expert panel was convened to consider minimal requirements for conducting and reporting the results of human whole-room indirect calorimeter studies. We propose Room Indirect Calorimetry Operating and Reporting Standards, version 1.0 (RICORS 1.0) to provide guidance to ensure consistency and facilitate meaningful comparisons of human energy metabolism studies across publications, laboratories, and clinical sites.

OBJECTIVE This study aimed to investigate a novel approach for determining the effects of energy-standardized dinner meals (high-fat and low-fat) on respiratory exchange ratio (RER) dynamics and metabolic flexibility. METHODS Using a randomized crossover study design, energy expenditure, RER, and macronutrient oxidation rates were assessed in response to a single dinner meal during an overnight stay in a whole-body room calorimeter. Eight healthy adults completed two overnight chamber stays while fed either a high-fat (60% fat, 20% carbohydrate [CHO], 20% protein; food quotient [FQ] = 0.784) or low-fat (20% fat, 60% CHO, 20% protein; FQ = 0.899) dinner containing 40% of daily energy requirements. RESULTS Following the low-fat meal, CHO oxidation first increased before decreasing, resulting in a 12-hour RER:FQ ratio close to 1.0 (0.986 ± 0.019, P = 0.06) and therefore resulting in a 12-hour equilibrated fat balance (29 ± 76 kcal/12 hours). Following the high-fat meal, participants had a RER:FQ ratio above 1.0 (1.061 ± 0.017, P

Over the past 10 to 15 years, intermittent fasting has emerged as an unconventional approach to reduce body weight and improve metabolic health beyond simple calorie restriction. In this review, we summarize findings related to Ramadan and Sunnah fasting. We then discuss the role of caloric restriction not only as an intervention for weight control, but importantly, as a strategy for healthy aging and longevity. Finally, we review the four most common intermittent fasting (IF) strategies used to date for weight management and to improve cardiometabolic health. Weight loss is common after IF, but does not appear to be different than daily caloric restriction when compared directly. IF may also provide additional cardiometabolic benefit, such as insulin sensitization, that is independent from weight loss. While no specific fasting regimen stands out as superior at this time, there is indeed heterogeneity in responses to these different IF diets. This suggests that one dietary regimen may not be ideally suited for every individual. Future studies should consider strategies for tailoring dietary prescriptions, including IF, based on advanced phenotyping and genotyping prior to diet initiation.

CONTEXT: Eating habits and food craving are strongly correlated with weight status. It is currently not well understood how psychological and behavioral factors influence both weight loss and weight regain. OBJECTIVE: To examine the associations between psychological and behavioral predictors with weight changes and energy intake in a randomized controlled trial on weight loss. DESIGN AND SETTING: The Prevention of Obesity Using Novel Dietary Strategies is a dietary intervention trial that examined the efficacy of 4 diets on weight loss over 2 years. Participants were 811 overweight (body mass index, 25-40.9 kg/m(2); age, 30-70 years) otherwise healthy adults. RESULTS: Every 1-point increase in craving score for high-fat foods at baseline was associated with greater weight loss (-1.62 kg, P = .0004) and a decrease in energy intake (r = -0.10, P = .01) and fat intake (r = -0.16, P

Objective This study aimed to describe the energy expenditure (EE) and macronutrient oxidation response to an individualized nonshivering cold exposure in young healthy adults. Methods Two different groups of 44 (study 1: 22.1 [SD 2.1] years old, 25.6 [SD 5.2] kg/m(2), 34% men) and 13 young healthy adults (study 2: 25.6 [SD 3.0] years old, 23.6 [SD 2.4] kg/m(2), 54% men) participated in this study. Resting metabolic rate (RMR) and macronutrient oxidation rates were measured by indirect calorimetry under fasting conditions in a warm environment (for 30 minutes) and in mild cold conditions (for 65 minutes, with the individual wearing a water-perfused cooling vest set at an individualized temperature adjusted to the individual's shivering threshold). Results In study 1, EE increased in the initial stage of cold exposure and remained stable for the whole cold exposure (P < 0.001). Mean cold-induced thermogenesis (9.56 +/- 7.9 kcal/h) was 13.9% +/- 11.6% of the RMR (range: -14.8% to 39.9% of the RMR). Carbohydrate oxidation decreased during the first 30 minutes of the cold exposure and later recovered up to the baseline values (P < 0.01) in parallel to opposite changes in fat oxidation (P < 0.01). Results were replicated in study 2. Conclusions A 1-hour mild cold exposure individually adjusted to elicit maximum nonshivering thermogenesis induces a very modest increase in EE and a shift of macronutrient oxidation that may underlie a shift in thermogenic tissue activity. This study was supported by the Spanish Ministry of Economy and Competitiveness via the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III (PI13/01393 and PTA 12264-I); the Retos de la Sociedad (DEP2016-79512-R) and European Regional Development Funds (ERDF); the Spanish Ministry of Education (FPU13/04365, FPU14/04172, and FPU15/04059); the Fundacion Iberoamericana de Nutricion; the Redes Tematicas de Investigacion Cooperativa (RETIC, red de Salud Materno Infantil y del Desarrollo 16/0022); the AstraZeneca HealthCare Foundation; the University of Granada Plan Propio de Investigación 2016 excellence actions (Unit of Excellence on Exercise and Health and Plan Propio de Investigacion 2018: Programa Contratos-Puente and Programa Perfeccionamiento de Doctores); the Junta de Andalucía, Consejeria de Conocimiento, Investigación y Universidades (ERDF; SOMM17/6107/UGR); and the Fundación Alfonso Maríin Escudero.

BACKGROUND: An ability to switch between primarily oxidizing fat in the fasted state to carbohydrate in the fed state, termed metabolic flexibility, is associated with insulin sensitivity. Metabolic flexibility has been explored previously in women with polycystic ovary syndrome (PCOS), yet the independent or synergistic contributions of androgen excess and/or insulin resistance is not yet known. Therefore, the purpose of this article was to characterize metabolic flexibility in women with PCOS compared to women of normal BMI, obesity, or type 2 diabetes (T2DM). METHODS: Eighty-six weight-stable women; thirty with either PCOS (n = 30), or fifty-six with obesity (n = 12), T2DM (n = 27), or normal BMI (n = 17) underwent a hyperinsulinemic euglycemic clamp and indirect calorimetry to measure insulin sensitivity and substrate oxidation via indirect calorimetry, respectively. RESULTS: All analyses were adjusted for differences in age, ethnicity, and BMI between groups. Women with PCOS were less metabolically flexible compared to healthy women with obesity (p

Metabolic flexibility to lipid (MetFlex-lip) is the capacity to adapt lipid oxidation to lipid availability. Hypothetically, impaired MetFlex-lip in skeletal muscle induces accumulation of lipid metabolites that interfere with insulin signaling. Our aim was to compare MetFlex-lip during exercise in subjects with low (Low_IS) vs. high (High_IS) insulin sensitivity. Twenty healthy men were designated as Low_IS or High_IS on the basis of the median of the homeostatic model assessment of insulin resistance index. Groups had similar age, body mass index, and maximum oxygen uptake (V̇o2max). Subjects cycled at 50% V̇o2max until expending 650 kcal. Adaptation in lipid oxidation was calculated as the drop in respiratory quotient (RQ) at the end of exercise vs. the maximum RQ (ΔRQ). Lipid availability was calculated as the increase in circulating nonesterified fatty acids (NEFA) at the end of exercise vs. the minimum NEFA (ΔNEFA). ΔRQ as a function of ΔNEFA was used to determine MetFlex-lip. On average, RQ and circulating NEFA changed similarly in both groups. However, ΔRQ correlated with ΔNEFA in High_IS ( r = −0.83, P < 0.01) but not in Low_IS ( r = −0.25, P = 0.48) subjects. Thus the slope of the ΔRQ vs. ΔNEFA relationship was steeper in High_IS vs. Low_IS subjects (−0.139 ± 0.03 vs. −0.025 ± 0.03 RQ·mmol−1·l−1, respectively; P < 0.05), with similar intercepts. We conclude that in subjects with High_IS lipid-to-carbohydrate oxidation ratio adapts to the increased circulating NEFA availability during exercise. Such MetFlex-lip appears impaired in subjects with Low_IS. Whether a cause-effect relationship exists between impaired MetFlex-lip and low insulin sensitivity remains to be determined.

The storage of lipids in the form of triglycerides (TGs) and the de novo synthesis (lipogenesis) of fatty acids from nonlipid precursors [de novo lipogenesis (DNL)] are important functions of adipose tissue (AT) that influence whole-body metabolism. Yet, few studies have reported in vivo estimates of adipose lipid kinetics in humans. Fifty-two women with obesity (27 African-American and 25 Caucasian; 29.7 ± 5.5 years; BMI 32.2 ± 2.8 kg/m(2); 44.3 ± 4.0% body fat) were enrolled in the study. In vivo synthesis (or replacement) of TGs (f(TG)) as well as the synthesis of the fatty acid, palmitate [a measure of adipose DNL (f(DNL))], were assessed using an 8 week incorporation of deuterium into lipids (glycerol and palmitate moieties of TGs) in subcutaneous abdominal (scABD) and subcutaneous femoral (scFEM) AT. We report, for the first time, significant race differences in both TG synthesis and absolute DNL, with Caucasians having higher f(TG) and f(DNL) as compared with African-Americans. The DNL contribution to newly synthesized TG (corrected f(DNL)) was not different between races. Interestingly, our findings also show that the scFEM adipose depot had higher TG replacement rates relative to the scABD. Finally, the replacement rate of TG (f(TG)) was negatively correlated with changes in body weight over the 8 week labeling period. Our results provide the first evidence that in vivo TG replacement (synthesis and breakdown) rates differ by ethnicity. In addition, TG turnover varies by depot location in humans, implying an increased capacity for TG storage and higher lipolytic activity in the scFEM AT.

To date, human studies show that brown adipose tissue (BAT) contributes a small yet highly variable amount to overall energy expenditure. No studies have shown a decrease in body weight with cold-induced BAT activation, and existing pharmacological studies suggest that BAT activation via the sympathetic nervous system may result in increased heart rate and systolic blood pressure. Furthermore, even though the amount and/or activity of BAT have been shown to vary with seasons, such variation does not seem to be translated into weight changes. Collectively, these findings do not support the use of BAT activation for weight loss in humans; however, the potential role of BAT in counteracting the metabolic adaptation observed with weight loss is suggested. Although the role of BAT in weight control is currently unsubstantiated, BAT may play a role in improving insulin sensitivity in humans.

OBJECTIVE This study aimed to identify factors that may predispose women to excess gestational weight gain (GWG). METHODS Seventy-two healthy women with obesity (30 class I, 24 class II, 18 class III) expecting a singleton pregnancy were studied at 13 to 16 weeks gestation. Energy expenditure (EE) was measured during sleep (SleepEE, average EE from 0200-0500 hours) in a whole-room calorimeter, and total daily EE (TDEE) over 7 days using doubly labeled water. Glucose, insulin, thyroid hormones, and catecholamines were measured. RESULTS Body composition explained 70% variability in SleepEE, and SleepEE accounted for 67% to 73% of TDEE. Though there was no evidence of consistent low metabolism, there was considerable variability. Low SleepEE was associated with insulin resistance and low triiodothyronine concentrations (both P = 0.01). Physical activity level was 1.47 ± 0.02. For women with SleepEE within 100 kcal/d of their predicted EE, TDEE was significantly less than the estimate (2,530 ± 91 vs. 2,939 kcal/d; P

We previously showed that fetal exposure to maternal type 1 diabetes (T1D) is associated with altered glucose-stimulated insulin secretion in adult offspring. Here, we investigated whether this β-cell defect displays a sex dimorphism. Twenty-nine adult nondiabetic offspring of T1D mothers (ODMs) were compared with 29 nondiabetic offspring of T1D fathers. We measured early insulin secretion in response to oral glucose and insulin secretion rate in response to intravenous glucose ramping. Insulin sensitivity and body composition were assessed by a euglycemic, hyperinsulinemic clamp and dual-energy X-ray absorptiometry, respectively. In response to oral glucose, male and female ODMs displayed a reduced insulin secretion. In contrast, in response to graded intravenous glucose infusion, only female ODMs (not males) exhibited decreased insulin secretion. There was no defect in response to combined intravenous arginine and glucose, suggesting that male and female ODMs exhibit a functional β-cell defect rather than a reduced β-cell mass. In conclusion, fetal exposure to maternal diabetes predisposes to β-cell dysfunction in adult male and female offspring. This β-cell defect is characterized by a sexual dimorphism following intravenous glucose stimulation., Insulin secretion was evaluated in adults who have been exposed in utero to maternal T1D. Only women (not men) exhibited decreased insulin secretion in response to intravenous glucose.

A noninvasive method to estimate muscle mass based on creatine ( methyl-d3) (D3-creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58–76 yr old) fasted overnight and then received an oral 30-mg dose of D3-creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3–4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography–tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D3-creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = −3.00 ± 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 ± 3.7 kg). However, intraindividual variability was high with the D3-creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D3-creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d3) (D3-creatine) and D3-creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D3-creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less bias than DXA. However, intraindividual variability is high with the D3-creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted.

While the first reported case of SARS-CoV-2 occurred in Wuhan, China, in December 2019, giving the name to the disease COVID-19, the World Health Organization declared this a Public Health Emergency of International Concern on January 30, 2020, and a pandemic on March 11, 2020 Persons with obesity indeed have increased rates of comorbid conditions, often have impaired immune responses to viral threats and abnormal proinflammatory and prothrombotic profiles, and experience stigma in health care settings where they are at a disadvantage because of their size (limited use of diagnostic equipment and therapeutic maneuvers), all factors driving COVID-19 complications and mortality (1) [ ]the annual Obesity Journal Symposium was held virtually at ObesityWeek with an outstanding and diverse group of papers and young scientists presenting their work

Reduced mitochondrial capacity in skeletal muscle has been observed in obesity and type 2 diabetes. In humans, the aetiology of this abnormality is not well understood but the possibility that it is secondary to the stress of nutrient overload has been suggested. To test this hypothesis, we examined whether sustained overfeeding decreases skeletal muscle mitochondrial content or impairs function. Twenty-six healthy volunteers (21 men, 5 women, age 25.3 ± 4.5 years, BMI 25.5 ± 2.4 kg/m2) underwent a supervised protocol consisting of 8 weeks of high-fat overfeeding (40% over baseline energy requirements). Before and after overfeeding, we measured systemic fuel oxidation by indirect calorimetry and performed skeletal muscle biopsies to measure mitochondrial gene expression, content and function in vitro. Mitochondrial function in vivo was measured by 31P NMR spectroscopy. With overfeeding, volunteers gained 7.7 ± 1.8 kg (% change 9.8 ± 2.3). Overfeeding increased fasting NEFA, LDL-cholesterol and insulin concentrations. Indirect calorimetry showed a shift towards greater reliance on lipid oxidation. In skeletal muscle tissue, overfeeding increased ceramide content, lipid droplet content and perilipin-2 mRNA expression. Phosphorylation of AMP-activated protein kinase was decreased. Overfeeding increased mRNA expression of certain genes coding for mitochondrial proteins (CS, OGDH, CPT1B, UCP3, ANT1). Despite the stress of nutrient overload, mitochondrial content and mitochondrial respiration in muscle did not change after overfeeding. Similarly, overfeeding had no effect on either the emission of reactive oxygen species or on mitochondrial function in vivo. Skeletal muscle mitochondria are significantly resilient to nutrient overload. The lower skeletal muscle mitochondrial oxidative capacity in human obesity is likely to be caused by reasons other than nutrient overload per se. ClinicalTrials.gov NCT01672632.

Objective Intramyocellular lipid (IMCL) is inversely related to insulin sensitivity in sedentary populations, yet no prospective studies in humans have examined IMCL accumulation with overfeeding. Methods Twenty-nine males were overfed a high-fat diet (140% caloric intake, 44% from fat) for 8 weeks. Measures of IMCL, whole-body fat oxidation from a 24-hour metabolic chamber, muscle protein extracts, and muscle ceramide measures were obtained before and after the intervention. Results Eight weeks of overfeeding did not increase overall IMCL. The content of smaller lipid droplets peripherally located in the myofiber decreased, while increases in larger droplets correlated inversely with glucose disposal rate. Overfeeding resulted in inhibition of Akt activity, which correlated with the reductions in smaller, peripherally located lipid droplets and drastic increases in ceramide content. Additionally, peripherally located lipid droplets were associated with more efficient lipid oxidation. Finally, participants who maintained a greater number of smaller, peripherally located lipid droplets displayed a better resistance to weight gain with overfeeding. Conclusions These results show that lipid droplet size and location rather than mere IMCL content are important to understanding insulin sensitivity.

Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this "upward setting" or "resetting" of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences.

Context Weight loss is prescribed to offset the deleterious consequences of polycystic ovary syndrome (PCOS), but a successful intervention requires an accurate assessment of energy requirements. Objective Describe energy requirements in women with PCOS and evaluate common prediction equations compared with doubly labeled water (DLW). Design Cross-sectional study. Setting Academic research center. Participants Twenty-eight weight-stable women with PCOS completed a 14-day DLW study along with measures of body composition and resting metabolic rate and assessment of physical activity by accelerometry. Main Outcome Total daily energy expenditure (TDEE) determined by DLW. Results TDEE was 2661 ± 373 kcal/d. TDEE estimated from four commonly used equations was within 4% to 6% of the TDEE measured by DLW. Hyperinsulinemia (fasting insulin and homeostatic model assessment of insulin resistance) was associated with TDEE estimates from all prediction equations (both r = 0.45; P = 0.02) but was not a significant covariate in a model that predicts TDEE. Similarly, hyperandrogenemia (total testosterone, free androgen index, and dehydroepiandrosterone sulfate) was not associated with TDEE. In weight-stable women with PCOS, the following equation derived from DLW can be used to determine energy requirements: TDEE (kcal/d) = 438 - [1.6 * Fat Mass (kg)] + [35.1 * Fat-Free Mass (kg)] + [16.2 * Age (y)]; R2 = 0.41; P = 0.005. Conclusions Established equations using weight, height, and age performed well for predicting energy requirements in weight-stable women with PCOS, but more precise estimates require an accurate assessment of physical activity. Our equation derived from DLW data, which incorporates habitual physical activity, can also be used in women with PCOS; however, additional studies are needed for model validation.

Background/Objective Impairments in metabolic flexibility and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured metabolic flexibility and substrate handling before and after 8 weeks of overfeeding in initially healthy adults, as a model of the early stages of insulin resistance. Subjects/Methods Twenty-nine healthy men (27 ± 5 years old; BMI 25.5 ± 2.3 kg/m2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6 ± 2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation, and metabolic flexibility were measured in 2 ways: a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter, and b) during a two-step hyperinsulinemic-euglycemic clamp. Results Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (p=0.001 and p=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (0.877 ± 0.020 to 0.864 ± 0.026; p=0.05) and at low insulin levels during the clamp (0.927 ± 0.047 to 0.907 ± 0.032; p=0.01). Overfeeding did not affect metabolic flexibility as measured during a clamp (p≥0.17), but it tended to increase 24-hour metabolic flexibility (awake – sleep RQ) as measured by chamber by 0.010 ± 0.028 (p=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation (13 ± 23 g/day; p=0.003) and tended to increase fat oxidation (6 ± 16 g/day; p=0.07), but did not affect carbohydrate oxidation (p=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, p=8×10−5) but not fat oxidation rates (p=0.09). Conclusions The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Context Adipose tissue (AT) expansion occurs by hypertrophy and hyperplasia. Impaired hyperplasia, or adipogenesis, has been associated with obesity-related diseases. Objective We examined how in vivo adipogenesis in the subcutaneous abdominal (scABD) and femoral (scFEM) depots (via 8-week incorporation of deuterium) correlates with markers of metabolic health. Design Data from 52 women with obesity [27 black and 25 white; 29.7 ± 5.5 years; body mass index (BMI) 32.2 ± 2.8 kg/m2; 44.3% ± 4.0% body fat] were analyzed at Pennington Biomedical Research Center. Main Outcomes A linear repeated measure model was used to assess the fraction of new adipose cells and the associated covariates. Akaike information criterion determined the covariates that best described the data. Simple associations were examined using Spearman's correlation. Results The covariates that were associated with adipose kinetics included BMI, visceral AT/total abdominal AT (VAT/TAT) ratio, and the Matsuda index. Simple correlations demonstrated that adipocyte and preadipocyte formation in scABD (P = 0.02 and P = 0.16, trend, respectively) and scFEM (P = 0.01 and P = 0.24, trend, respectively) depots correlated positively with VAT/TAT. Preadipocyte and adipocyte formation in the scABD (P < 0.0001 and P = 0.02, respectively) and scFEM (P = 0.0001 and P = 0.003, respectively) was negatively associated with insulin sensitivity. Conclusions Our results challenge the AT expandability hypothesis and suggest that higher in vivo adipose cell turnover is positively associated with BMI and VAT/TAT and negatively associated with insulin sensitivity, all correlates of impaired metabolic health.

Objective Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet-induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans. Methods Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/m2) were overfed by 40% for 8 weeks. Before and after, energy expenditure and metabolic adaptation were measured by whole-room respiratory calorimetry. A marker of BAT activity was measured using infrared imaging of the supraclavicular BAT depot. Results At the end of 8 weeks of overfeeding, metabolic adaptation—defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain—rose from −0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51). Conclusions BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.

ObjectiveThe rs8004664 variation within the FOXN3 gene is significantly and independently associated with fasting blood glucose in humans. We have previously shown that the hyperglycemia risk allele (A) increases FOXN3 expression in primary human hepatocytes; over-expression of human FOXN3 in zebrafish liver increases fasting blood glucose; and heterozygous deletion of the zebrafish orthologfoxn3decreases fasting blood glucose. Paralleling these model organism findings, we found that rs8004664 A|A homozygotes had blunted glucagon suppression during an oral glucose tolerance test. Here, we test associations between insulin sensitivity and the rs8004664 variation.Research design and methods92 participants (49±13 years, body mass index: 32±6 kg/m2, 28 with and 64 without type 2 diabetes mellitus) were genotyped at rs8004664. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp technique.ResultsThe “A” allele frequency was 59%; the protective (G) allele frequency was 41% (A|A: n=29; G|G: n=12; A|G: n=50). Clamp-measured glucose disposal rate (GDR) was not different by genotype (F=0.046, p=0.96) or by “A” allele carrier (p=0.36). Female G|G homozygotes had better insulin sensitivity compared to female “A” allele carriers (GDR; G|G: 9.9±3.0 vs A|A+A|G: 7.1±3.0 mg/kg fat-free mass+17.7/min; p=0.04). Insulin sensitivity was not different by genotype or by “A” allele carriers.ConclusionThe rs8004664 variation within the FOXN3 gene may modulate insulin sensitivity in women.

Aims To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole-orange (Citrus sinensis) extract. Methods and methods In a single-ascending-dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least 1 week. Blood safety markers were evaluated pre-dose and 24 hours post-dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four- and 24-hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed-effects linear model. Results There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 μM (NAR150) and 48.45 ± 7.88 μM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24-hour concentration-time curve: 67.61 ± 24.36 μM × h (NAR150) and 199.05 ± 24.36 μM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half-life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 μM (4 hours) and 0.35 ± 0.30 μM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 μM (4 hours) and 0.24 ± 0.30 μM (24 hours). Conclusions Ingestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 μM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.

The present "obesogenic' environment has favored excessive energy intake resulting in the current obesity epidemic and its associated diseases. The epidemic has incentivized scientists to develop novel behavioral and pharmacological strategies that enhance energy expenditure to compensate for excessive energy intake. Although physical activity is effective to increase total energy expenditure, it is insufficient to induce negative energy balance and weight loss. With the discovery of brown adipose tissue (BAT) in adult humans, BAT activation soon emerged as a potential strategy for elevating energy expenditure. BAT is the only tissue that expresses uncoupling protein 1, conferring on this tissue high thermogenic capacity due to a low efficiency for mitochondrial ATP generation. Potential manipulation of BAT mass and activity has fueled the interest in altering whole-body energy balance through increased energy expenditure. Remarkable advances have been made in quantifying the amount and activity of BAT in humans. Many studies have concluded that the amount of active BAT appears insufficient to induce meaningful increases in energy expenditure. Thus, the majority of studies report that BAT activation does not influence body weight and metabolic control in humans. Strategies to increase BAT mass and/or to potentiate BAT activity seem necessary.

BACKGROUND: Metabolic flexibility can be assessed by changes in respiratory exchange ratio (RER) following feeding. Though metabolic flexibility (difference in RER between fasted and fed state) is often impaired in individuals with obesity or type 2 diabetes, the cellular processes contributing to this impairment are unclear. MATERIALS AND METHODS: From several clinical studies we identified the 16 most and 14 least metabolically flexible male and female subjects out of >100 participants based on differences between 24-hour and sleep RER measured in a whole-room indirect calorimeter. Global skeletal muscle gene expression profiles revealed that, in metabolically flexible subjects, transcripts regulated by the RNA binding protein, HuR, are enriched. We generated and characterized mice with a skeletal muscle-specific knockout of the HuR encoding gene, Elavl1 (HuR(m−/−)). RESULTS: Male, but not female, HuR(m−/−) mice exhibit metabolic inflexibility, with mild obesity, impaired glucose tolerance, impaired fat oxidation and decreased in vitro palmitate oxidation compared to HuR(fl/fl) littermates. Expression levels of genes involved in mitochondrial fatty acid oxidation and oxidative phosphorylation are decreased in both mouse and human muscle when HuR is inhibited. CONCLUSIONS: HuR inhibition results in impaired metabolic flexibility and decreased lipid oxidation, suggesting a role for HuR as an important regulator of skeletal muscle metabolism.

Background: COVID-19 acute viral pulmonary infection has been associated with cytokine storm syndrome and resultant acute lung injury in severe cases Ferritin and d-dimer levels have been used to make clinical decisions in an effort to correct these derangements Patients with obesity seemed especially vulnerable with this mechanism given their predisposition to an elevated inflammatory state The aim of this study is to further describe the inflammatory profile of patients with obesity and report outcomes Methods: A cohort of 600 COVID-19 positive admitted patients from March 2020-May 2020 was examined Patients were stratified by WHO obesity class Presenting symptoms, disease biomarkers, demographics, and outcomes were investigated Results: Age was found to be inversely related to the obesity class (Normal weight 63 9 years, overweight 61 5, obese 58 7, severely obese 54 4, morbidly obese 51 0;p

Cardiotrophin-1 (CT-1) is a gp130 cytokine that was previously characterized for its effects on cardiomyocytes and identified as a marker of heart failure. More recent studies reported elevated circulating levels of CT-1 in humans with obesity and metabolic syndrome (MetS). However, a subsequent rodent study implicated CT-1 as a potential therapeutic target for obesity and MetS. Adipose tissue (AT) is broadly acknowledged as an endocrine organ and is a substantial source of CT-1. However, no study has examined the expression of adipose-derived CT-1 in humans. We present the first analysis of CT-1 mRNA expression in subcutaneous AT and its association with clinical variables in 22 women with obesity and 15 men who were 40% overfed for 8-weeks. We observed that CT-1 expression was higher in the subcutaneous abdominal (scABD) than the femoral (scFEM) depot. Importantly, we reveal that scFEM but not scABD, CT-1 expression was negatively associated with visceral adiposity and intrahepatic lipid, while positively correlated with insulin sensitivity in obese women. Also, men with higher CT-1 levels at baseline had less of a decline in insulin sensitivity in response to overfeeding. Our data provide new knowledge on the regulation of adipose-derived CT-1 in obesity and during weight gain in response to overfeeding in humans and suggest that CT-1 may play a protective role in obesity and related disorders.

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. Invitro and invivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.

Summary Background For several cardiometabolic risk factors, values considered within normal range are associated with an increased risk of cardiovascular morbidity and mortality. We aimed to investigate the short-term and long-term effects of calorie restriction with adequate nutrition on these risk factors in healthy, lean, or slightly overweight young and middle-aged individuals. Methods CALERIE was a phase 2, multicentre, randomised controlled trial in young and middle-aged (21–50 years), healthy non-obese (BMI 22·0–27·9 kg/m2) men and women done in three clinical centres in the USA. Participants were randomly assigned (2:1) to a 25% calorie restriction diet or an ad libitum control diet. Exploratory cardiometabolic risk factor responses to a prescribed 25% calorie restriction diet for 2 years were evaluated (systolic, diastolic, and mean blood pressure; plasma lipids; high-sensitivity C-reactive protein; metabolic syndrome score; and glucose homoeostasis measures of fasting insulin, glucose, insulin resistance, and 2-h glucose, area-under-the curve for glucose, and insulin from an oral glucose tolerance test) analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00427193. Findings From May 8, 2007, to Feb 26, 2010, of 238 participants that were assessed, 218 were randomly assigned to and started a 25% calorie restriction diet (n=143, 66%) or an ad libitum control diet (n=75, 34%). Individuals in the calorie restriction group achieved a mean reduction in calorie intake of 11·9% (SE 0·7; from 2467 kcal to 2170 kcal) versus 0·8% (1·0) in the control group, and a sustained mean weight reduction of 7·5 kg (SE 0·4) versus an increase of 0·1 kg (0·5) in the control group, of which 71% (mean change in fat mass 5·3 kg [SE 0·3] divided by mean change in weight 7·5 kg [0·4]) was fat mass loss. Calorie restriction caused a persistent and significant reduction from baseline to 2 years of all measured conventional cardiometabolic risk factors, including change scores for LDL-cholesterol (p Interpretation 2 years of moderate calorie restriction significantly reduced multiple cardiometabolic risk factors in young, non-obese adults. These findings suggest the potential for a substantial advantage for cardiovascular health of practicing moderate calorie restriction in young and middle-aged healthy individuals, and they offer promise for pronounced long-term population health benefits. Funding National Institute on Aging and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Objective Eating earlier in the daytime to align with circadian rhythms in metabolism enhances weight loss. However, it is unknown whether these benefits are mediated through increased energy expenditure or decreased food intake. Therefore, this study performed the first randomized trial to determine how meal timing affects 24-hour energy metabolism when food intake and meal frequency are matched. Methods Eleven adults with overweight practiced both early time-restricted feeding (eTRF) (eating from 8 am to 2 pm) and a control schedule (eating from 8 am to 8 pm) for 4 days each. On the fourth day, 24-hour energy expenditure and substrate oxidation were measured by whole-room indirect calorimetry, in conjunction with appetite and metabolic hormones. Results eTRF did not affect 24-hour energy expenditure (Δ = 10 ± 16 kcal/d; P = 0.55). Despite the longer daily fast (intermittent fasting), eTRF decreased mean ghrelin levels by 32 ± 10 pg/mL (P = 0.006), made hunger more even-keeled (P = 0.006), and tended to increase fullness (P = 0.06-0.10) and decrease the desire to eat (P = 0.08). eTRF also increased metabolic flexibility (P = 0.0006) and decreased the 24-hour nonprotein respiratory quotient (Δ = -0.021 ± 0.010; P = 0.05). Conclusions Meal-timing interventions facilitate weight loss primarily by decreasing appetite rather than by increasing energy expenditure. eTRF may also increase fat loss by increasing fat oxidation.

IMPACT: A short treatment of 8 obese postmenopausal women with conjugated estrogens and bazedoxifene does not alter insulin sensitivity or ectopic fat but increases serum markers of hepatic de novo lipogenesis and production of triacylglycerides. OBJECTIVES/GOALS: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally-administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. METHODS/STUDY POPULATION: We conducted a randomized, double-blind, crossover pilot trial, testing the effect of CE/BZA on cardiometabolic health in postmenopausal women. Eight postmenopausal women (age 50-60 y, BMI 30-40 kg/m2) were randomization to an 8-week CE/BZA or placebo treatment separated by an 8-week washout period [NCT02274571]. The primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp), while secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); inflammatory markers; and serum metabolome (LC/MS). RESULTS/ANTICIPATED RESULTS: CE/BZA had no effect on insulin sensitivity, body composition, ectopic fat, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: p=0.06; high-dose clamp: p=0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs), and decreased long-chain acylcarnitines. These findings possibly reflect increased hepatic de novo FA synthesis and esterification into TAGs, and decreased FA oxidation, respectively (p

Obesity is a physiological condition of chronic positive energy balance. While the regulation of energy metabolism varies widely among individuals, identifying those who are metabolically prone to weight gain and intervening accordingly is a key challenge for reversing the course of the obesity epidemic. Indirect calorimetry is the most commonly used method to measure energy expenditure in the research setting. By measuring oxygen consumption and carbon dioxide production, indirect calorimetry provides minute-by-minute energy expenditure data that makes it the most valuable tool to distinguish the various components of energy expenditure, that is, sleeping and resting metabolic rate, thermic effect of food and the energy cost of activity. Importantly, such measures also provide information on energy substrate utilization. Here we summarized some of the research that revealed resting metabolic rate, spontaneous physical activity and respiratory quotient as key metabolic predictors of weight gain and obesity. Recent studies using indirect calorimetry in response to mid-term fasting or overfeeding have identified 'thrifty' and 'spendthrift' phenotypes in people who differ in propensity to weight gain. We propose the use of indirect calorimetry data as a basis for personalized interventions that may be efficacious in slowing down the rise of global obesity.

CONTEXT: It is not known whether the magnitude of metabolic adaptation, a greater than expected drop in energy expenditure, depends on the type of bariatric surgery and is associated with cardiometabolic improvements. OBJECTIVE: To compare changes in energy expenditure (metabolic chamber) and circulating cardiometabolic markers 8 weeks and 1 year after Roux-en-y bypass (RYGB), sleeve gastrectomy (SG), laparoscopic adjustable gastric band (LAGB), or a low-calorie diet (LCD). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: This was a parallel-arm, prospective observational study of 30 individuals (27 females; mean age, 46 ± 2 years; body mass index, 47.2 ± 1.5 kg/m(2)) either self-selecting bariatric surgery (five RYGB, nine SG, seven LAGB) or on a LCD (n = 9) intervention (800 kcal/d for 8 weeks, followed by weight maintenance). RESULTS: After 1 year, the RYGB and SG groups had similar degrees of body weight loss (33–36%), whereas the LAGB and LCD groups had 16 and 4% weight loss, respectively. After adjusting for changes in body composition, 24-hour energy expenditure was significantly decreased in all treatment groups at 8 weeks (−254 to −82 kcal/d), a drop that only persisted in RYGB (−124 ± 42 kcal/d; P = .002) and SG (−155 ± 118 kcal/d; P = .02) groups at 1 year. The degree of metabolic adaptation (24-hour and sleeping energy expenditure) was not significantly different between the treatment groups at either time-point. Plasma high-density lipoprotein and total and high molecular weight adiponectin were increased, and triglycerides and high-sensitivity C-reactive protein levels were reduced 1 year after RYGB or SG. CONCLUSIONS: Metabolic adaptation of approximately 150 kcal/d occurs after RYGB and SG surgery. Future studies are required to examine whether these effects remain beyond 1 year.

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 {"type":"clinical-trial","attrs":{"text":"NCT01967563","term_id":"NCT01967563"}}NCT01967563.

OBJECTIVE To conduct a secondary analysis designed to test whether gestational weight gain is the result of increased energy intake or adaptive changes in energy expenditures. METHODS In this secondary analysis, energy intake and energy expenditure of 45 pregnant women (body mass index [BMI] 18.5-24.9 [n=33] and BMI 25 or greater [n=12]) were measured preconceptionally and at 22 and 36 weeks of gestation. Energy intake was calculated as the sum of total energy expenditure measured by doubly-labeled water and energy deposition determined by the four-compartment body composition model. Measurements of weight, body composition, and basal metabolic rate were completed preconceptionally and 9, 22, and 36 weeks of gestation. Basal metabolic rate was measured by indirect calorimetry in a room calorimeter and activity energy expenditure by doubly-labeled water. RESULTS Energy intake from 22 to 36 weeks of gestation was significantly higher in high gainers (n=19) (3,437±99 kcal per day) compared with low+ideal gainers (n=26) (2,687±110, P

OBJECTIVE: On December 8-9, 2014, the Pennington Biomedical Research Center convened a scientific symposium to review the state-of-the-science and future directions for the study of developmental programming of obesity and chronic disease. The objectives of the symposium were to discuss: (i) past and current scientific advances in animal models, population-based cohort studies, and human clinical trials, (ii) the state-of-the-science of epigenetic-based research, and (iii) considerations for future studies.RESULTS: This symposium provided a comprehensive assessment of the state of the scientific field and identified research gaps and opportunities for future research in order to understand the mechanisms contributing to the developmental programming of health and disease.CONCLUSIONS: Identifying the mechanisms which cause or contribute to developmental programming of future generations will be invaluable to the scientific and medical community. The ability to intervene during critical periods of prenatal and early postnatal life to promote lifelong health is the ultimate goal. Considerations for future research including the use of animal models, the study design in human cohorts with considerations about the timing of the intrauterine exposure, and the resulting tissue-specific epigenetic signature were extensively discussed and are presented in this meeting summary. (Less)