One-year caloric restriction and 12-week exercise training intervention in obese adults with type 2 diabetes: emphasis on metabolic control and resting metabolic rate.

PURPOSE: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO2max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO2max in obese adults with type 2 diabetes. METHODS: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM). RESULTS: Compared with baseline, after 6 months we found significant increases in VO2max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO2max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups. CONCLUSIONS: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men.

BACKGROUND/OBJECTIVE: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF 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; body mass index 25.5±2.3 kg m-2) 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 MF were measured in two 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 (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day-1 (P=0.003) and tended to increase fat oxidation by 6±16 g day-1 (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.

Eight weeks of dietary overfeeding increases renal filtration rates in humans: implications for the pathogenesis of diabetic hyperfiltration.

OBJECTIVE: Diabetic nephropathy is characterized at its onset by glomerular hyperfiltration. Prospective studies in humans measuring filtration rates with weight gain are lacking. We investigated renal filtration following weight gain induced by overfeeding. DESIGN: Eight weeks of overfeeding (40% above energy requirements, 44% fat, 15% protein and 41% carbohydrate) as well as a 6-month follow-up after the overfeeding intervention. SUBJECTS: Thirty-five participants (age: 26.7 ±5.3 years; body mass index: 25.5 ± 2.2 kg m(-2) ; 29 m/6f). MEASUREMENTS: Creatinine clearance rate (Ccr) from 24-h urine collection, estimated glomerular filtration rate (eGFR) from the modification of diet in renal disease (MDRD), insulin sensitivity/glucose disposal rate (GDR) by a euglycemic-hyperinsulinemic clamp, components from basic metabolic panels and serum lipid panels. RESULTS: Both eGFR and Ccr increased with overfeeding (P = 0.04) and serum lipids (all P < 0.05), along with a decrease in insulin sensitivity (P = 0.003). Fasting glucose concentration was not affected (P = 0.98), but the per cent change in Ccr correlated positively with the change in GDR with overfeeding (r = 0.39, P = 0.02). Six months following overfeeding, serum glucose was maintained, and no evidence of urinary glucose was observed at any time-point. CONCLUSIONS: These data suggest that renal hyperfiltration may act as a mechanism to preserve insulin sensitivity through maintenance of systemic glucose homoeostasis with caloric excess.

Inverse correlation of serum inflammatory markers with metabolic parameters in healthy, Black and White prepubertal youth.

OBJECTIVE: To examine for the first time the associations between pro-inflammatory cytokines and obesity-related metabolic biomarkers in, exclusively prepubertal, otherwise healthy obese and non-obese Black and White children, 7-9 years of age. DESIGN AND METHODS: Body mass index (BMI), homeostasis model assessment-estimated insulin resistance, visceral adipose tissue and subcutaneous adipose tissue (SAT (magnetic resonance imaging)); total body fat (dual-energy X-ray absorptiometry), ectopic, intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) fat (proton magnetic resonance spectroscopy) and serum levels of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 were measured in 40 obese and non-obese children. Relationships between inflammatory cytokines and obesity were assessed by analysis of variance and Spearman's rank correlation. RESULTS: Significant inverse correlations were found between BMI z-score, SAT, total BF, and IHL and levels of TNF-α (Spearman's ρ=-0.36, -0.39, -0.43 and -0.39, respectively; P<0.05). Levels of IL-8 were significantly and inversely correlated with IMCL (-0.39; P=0.03) and remained significant after adjusting for race. IMCL was inversely associated with TNF-α only after adjusting for race (-0.37; P=0.04). CONCLUSIONS: Relationships between pro-inflammatory and metabolic markers commonly observed in adults are reversed in healthy, Black and White children before puberty. Prospective studies are warranted to determine how these inverse relationships modify chronic disease risk later in life.

No evidence for metabolic adaptation during exercise-related energy compensation.

The constrained energy model posits that the increased total daily energy expenditure (TDEE) in response to exercise is often less than the energy cost of the exercise prescribed. The mechanisms behind this phenomenon, coined "exercise-related energy compensation" (ExEC), are poorly understood, and it is unknown if ExEC is coupled with metabolic adaptation. Using a randomized controlled 24-week exercise intervention, individuals who demonstrated ExEC were identified. Changes to all components of TDEE and metabolic adaptation were assessed using doubly labeled water over 14 days and room calorimetry over 24-h 48% of individuals exhibited ExEC (-308 ± 158 kcals/day). There were no statistically significant differences in sex, age, or BMI between ExEC and non-ExEC. ExEC was associated with baseline TDEE (r = -0.50, p = 0.006). There were no statistically significant differences in metabolic adaptations for 24 h, sleep, or resting expenditures. These findings reveal that ExEC occurs independent of metabolic adaptation in sedentary components of EE.

Activity related energy expenditure, appetite and energy intake: potential implications for weight management.

The aim was to investigate relationships between activity related energy expenditure (AREE), appetite ratings and energy intake (EI) in a sample of 40 male (26.4years; BMI 23.5kg/m(2)) and 42 female (26.9years; BMI 22.4kg/m(2)) participants. AREE was expressed as the residual value of the regression between total daily EE (by doubly labeled water) and resting EE (by indirect calorimetry). EI was measured using an ad libitum buffet meal and visual analogue scales measured subjective appetite ratings before and after the meal. AREE was divided into low, middle and high sex-specific tertiles. General linear models were used to investigate differences in appetite ratings and EI across AREE tertiles. Before the meal, males in the high AREE tertile had significantly lower desire to eat and lower prospective food consumption and higher feelings of fullness compared to those in the low tertile. Males in the middle tertile had significantly higher satiety quotients after the meal and lower EI compared to the other tertiles. No significant differences across tertiles were found in females. Sex differences in relationships between AREE, appetite ratings and EI may lead to differing patterns of EI and subsequent weight maintenance.

Postprandial whole-body glycolysis is similar in insulin-resistant and insulin-sensitive non-diabetic humans.

AIMS/HYPOTHESIS: Insulin resistance is characterised by impaired glucose utilisation when measured by a euglycaemic-hyperinsulinaemic clamp. We hypothesised that, in response to postprandial conditions, non-diabetic individuals would have similar intracellular glycolytic and oxidative glucose metabolism independent of the degree of insulin resistance. METHODS: Fourteen (seven male) sedentary, insulin-sensitive participants (mean ± SD: BMI 25 ± 4 kg/m²; age 39 ± 10 years; glucose disposal rate 9.4 ± 2.1 mg [kg estimated metabolic body size]⁻¹ min⁻¹) and 14 (six male) sedentary, non-diabetic, insulin-resistant volunteers (29 ± 4 kg/m²; 34 ± 13 years; 5.3 ± 1.2 mg [kg estimated metabolic body size]⁻¹ min⁻¹) received after a 10 h fast 60 g glucose plus 15 g [6,6-²H2]glucose. Serum glucose and insulin concentrations, plasma ²H enrichment and whole-body gas exchange were determined before glucose ingestion and hourly thereafter for 4 h. Plasma ²H2O production is an index of glycolytic disposal. On day 2, participants received a weight-maintenance diet. On day 3, a euglycaemic-hyperinsulinaemic clamp was performed. RESULTS: Insulin-resistant individuals had about a twofold higher postprandial insulin response than insulin-sensitive individuals (p = 0.003). Resting metabolic rate was similar in the two groups before (p = 0.29) and after (p = 0.33-0.99 over time) glucose ingestion, whereas a trend for blunted glucose-induced thermogenesis was observed in insulin-resistant vs insulin-sensitive individuals (p = 0.06). However, over the 4 h after the 75 g glucose ingestion, glycolytic glucose disposal was the same in insulin-sensitive and insulin-resistant individuals (36.5 ± 3.7 and 36.2 ± 6.4 mmol, respectively; p = 0.99). Similarly, whole-body carbohydrate oxidation did not differ between the groups either before or after glucose ingestion (p = 0.41). CONCLUSIONS/INTERPRETATION: Postprandial hyperinsulinaemia and modest hyperglycaemia overcome insulin resistance by enhancing tissue glucose uptake and intracellular glucose utilisation.

Caloric restriction in humans reveals immunometabolic regulators of health span.

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.

Validity of four commercially available metabolic carts for assessing resting metabolic rate and respiratory exchange ratio in non-ventilated humans.

BACKGROUND & AIMS: The validity of most commercially available metabolic cart is mostly unknown. Thus, we aimed to determine the accuracy, precision, within-subject reproducibility, and concordance of RMR and RER measured by four commercially available metabolic carts [Cosmed Q-NRG, Vyaire Vyntus CPX, Maastricht Instruments Omnical, and Medgraphics Ultima CardiO2]. Further, we studied whether a previously proposed simulation-based post-calorimetric calibration of cart readouts [individual calibration control evaluation (ICcE)] modify the RMR and RER reproducibility and concordance. METHODS: Three experiments simulating different RMR and RER by controlled pure gas (N2 and CO2) infusions were conducted on 5 non-consecutive days. Moreover, 30-min methanol burns were performed on 3 non-consecutive days. Lastly, the RMR and RER of 29 young non-ventilated adults (11 women; 25 ± 4 years-old; BMI: 24.1 ± 3.2 kg/m2) were assessed twice using each instrument, 24 hours apart, under standardized conditions. RESULTS: The Omnical presented the lowest measurement error for RER (Omnical = 1.7 ± 0.9%; Vyntus = 4.5 ± 2.0%; Q-NRG = 6.6 ± 1.9%; Ultima = 6.8 ± 6.5%) and EE (Omnical = 1.5 ± 0.5%; Q-NRG = 2.5 ± 1.3%; Ultima = 10.7 ± 11.0%; Vyntus = 13.8 ± 5.0%) in all in vitro experiments (controlled pure gas infusions and methanol burns). In humans, the 4 metabolic carts provided discordant RMR and RER estimations (all P < 0.001). No differences were detected in RMR within-subject reproducibility (P = 0.058; Q-NRG inter-day coefficient of variance = 3.6 ± 2.5%; Omnical = 4.8 ± 3.5%; Vyntus = 5.0 ± 5.6%; Ultima = 5.7 ± 4.6%), although the Ultima CardiO2 provided larger RER inter-day differences (4.6 ± 3.5%) than the others carts (P = 0.001; Omnical = 1.9 ± 1.7%; Vyntus = 2.1 ± 1.3%; Q-NRG = 2.4 ± 2.1%). The ICcE procedure did not modify the RMR or RER concordance and did not reduce the inter-day differences in any of the carts. CONCLUSIONS: The 4 metabolic carts provided discordant measurements of RMR and RER. Overall, the Omnical provides more accurate and precise estimations of RMR and RER than the Q-NRG, Vyntus and Ultima CardiO2, and might be considered the best for assessing RMR and RER in non-ventilated humans. Finally, our results do not support the use of an ICcE procedure.

Intrahepatic and intramyocellular lipids are determinants of insulin resistance in prepubertal children.

AIMS/HYPOTHESIS: We hypothesised that ectopic fat deposition is present in liver and skeletal muscle before puberty and that both are potentially important factors in the early pathogenesis of insulin resistance. METHODS: Proton magnetic resonance spectroscopy was used to evaluate intramyocellular and intrahepatic lipids in 50 male and 42 female multi-ethnic, prepubertal (Tanner < 2) children (8.1 ± 0.8 years; 35.4 ± 10.7 kg; 27.9 ± 8.3% body fat; means ± SD). Intramyocellular lipid was measured in soleus muscle and intrahepatic lipid in the middle right lobe. Abdominal fat was measured by magnetic resonance imaging, body fat by dual energy X-ray absorptiometry, and insulin resistance using homeostatic model assessment. RESULTS: Intrahepatic lipid ranged from 0.11% to 4.6% relative to the liver water signal (mean 0.79 ± 0.79%) whereas intramyocellular lipid ranged from 0.13% to 1.86% relative to the muscle water signal (mean 0.51 ± 0.28%). Intramyocellular and intrahepatic lipids were significantly correlated with total adiposity (r = 0.49 and 0.59), abdominal adiposity (r = 0.44 and 0.54), and each other (r = 0.39, p < 0.05, Spearman). Both intramyocellular and intrahepatic lipid were positively correlated with fasting insulin (r = 0.37 and 0.38 respectively) and insulin resistance (r = 0.37 and 0.37; p < 0.01). After adjustment for race and sex, the relations between ectopic fat and insulin resistance remained, whereas both disappeared when further adjusted for body fat or BMI z scores. CONCLUSIONS/INTERPRETATIONS: These results suggest that typical relations between body composition, ectopic fat and insulin resistance are present in children before puberty. Thus, interventions aimed at reducing adiposity have the potential to decrease ectopic fat accumulation, delay the onset of insulin resistance and decrease the risk for development of type 2 diabetes in children.

Assessment of EchoMRI-AH versus dual-energy X-ray absorptiometry to measure human body composition.

BACKGROUND: The sensitivity to detect small changes in body composition (fat mass and fat-free mass) largely depends on the precision of the instrument. We compared EchoMRI-AH and dual-energy X-ray absorptiometry (DXA) (Hologic QDR-4500A) for estimating fat mass in 301 volunteers. METHODS: Body composition was evaluated in 136 males and 165 females with a large range of body mass index (BMI) (19-49 kg m(-2)) and age (19-91 years old) using DXA and EchoMRI-AH. In a subsample of 13 lean (BMI=19-25 kg m(-2)) and 21 overweight/obese (BMI>25 kg m(-2)) individuals, within-subject precision was evaluated from repeated measurements taken within 1 h (n=3) and 1 week apart (mean of three measurements taken on each day). RESULTS: Using Bland-Altman analysis, we compared the mean of the fat mass measurements versus the difference in fat mass measured by both instruments. We found that EchoMRI-AH quantified larger amount of fat versus DXA in non-obese (BMI<30 kg m(-2) (1.1 kg, 95% confidence interval (CI(95)):-3.7 to 6.0)) and obese (BMI ≥ 30 kg m(-2) (4.2 kg, CI(95):-1.4 to 9.8)) participants. Within-subject precision (coefficient of variation, %) in fat mass measured within 1 h was remarkably better when measured by EchoMRI-AH than DXA (<0.5 versus <1.5%, respectively; P<0.001). However, 1-week apart within-subject variability showed similar values for both instruments (<2.2%; P=0.15). CONCLUSIONS: EchoMRI-AH yielded greater fat mass values when compared with DXA (Hologic QDR-4500A), particularly in fatter subjects. EchoMRI-AH and DXA showed similar 1-week apart precision when fat mass was measured both in lean and overweight/obese individuals.

Relatively low plasma leptin concentrations precede weight gain in Pima Indians.

Leptin, the product of the ob gene, is a hormone, produced by adipose cells, that inhibits food intake and increases energy expenditure in rodents. In humans, plasma leptin concentrations correlate closely with the size of the adipose tissue depot; however, there is considerable variation in plasma leptin concentrations at any given degree of fatness. To investigate whether individuals prone to weight gain are hypoleptinemic, we measured fasting plasma leptin concentrations in two groups of weight-matched nondiabetic Pima Indians followed for approximately 3 years, 19 of whom subsequently gained weight and 17 of whom maintained their weight. After we adjusted for initial percent body fat, mean plasma leptin concentration was lower in those who gained weight than in those whose weight was stable. These data indicate that relatively low plasma leptin concentrations may play a role in the development of obesity in Pima Indians, a population prone to obesity.

Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects.

Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action.

OBJECTIVE: To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals. DESIGN: Cross-sectional inpatient study. SUBJECTS: Obese Pima Indians with normal glucose tolerance. MEASUREMENTS: Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1alpha, MIP1beta and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1alpha, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) (all n=34). RESULTS: MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action. CONCLUSIONS: Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

Effect of calorie restriction on subjective ratings of appetite.

BACKGROUND: Energy or calorie restriction (CR) has consistently been shown to produce weight loss and have beneficial health effects in numerous species, including primates and humans. Most individuals, however, are unable to sustain weight losses induced through reductions in energy intake, potentially due to increased hunger levels. The effects that prolonged CR has on subjective aspects of appetite have not been well studied. Thus, the present study tested the effect of 6 months of caloric restriction on appetite in healthy, overweight men and women. METHODS: Forty-eight overweight men and women with a body mass index (BMI; kg m(-2)) between 25-29.9 took part in a 6-month study and were randomised into one of four groups: healthy diet (control); 25% CR; 12.5% CR plus exercise (12.5% increased energy expenditure; CR + EX); low-calorie diet [LCD; 3724 kJ day(-1) (890 kcal day(-1)) until 15% of initial body weight was lost, then maintenance]. Appetite markers (i.e. hunger, fullness, desire to eat, etc.) were assessed weekly during a fasting state. RESULTS: Body weight was significantly reduced in all three energy-restricted groups (CR = -10.4 +/- 0.9%; CR + EX = -10.0 +/- 0.8%; and LCD = -13.9 +/-0.7%), indicating that participants were adherent to their energy restriction regimen, whereas the healthy diet control group remained weight stable (control = -1.0 +/- 1.1%). Despite these significant weight losses, appetite ratings of participants in the three energy-restricted groups at month 6 were similar to the weight stable control group. CONCLUSIONS: CR regimens with low fat diets producing significant weight losses have similar effects on appetite markers over a 6-month time period compared to a weight stable control group.

Energy metabolism, fuel selection and body weight regulation.

Energy homeostasis is critical for the survival of species. Therefore, multiple and complex mechanisms have evolved to regulate energy intake and expenditure to maintain body weight. For weight maintenance, not only does energy intake have to match energy expenditure, but also macronutrient intake must balance macronutrient oxidation. However, this equilibrium seems to be particularly difficult to achieve in individuals with low fat oxidation, low energy expenditure, low sympathetic activity or low levels of spontaneous physical activity, as in addition to excess energy intake, all of these factors explain the tendency of some people to gain weight. Additionally, large variability in weight change is observed when energy surplus is imposed experimentally or spontaneously. Clearly, the data suggest a strong genetic influence on body weight regulation implying a normal physiology in an 'obesogenic' environment. In this study, we also review evidence that carbohydrate balance may represent the potential signal that regulates energy homeostasis by impacting energy intake and body weight. Because of the small storage capacity for carbohydrate and its importance for metabolism in many tissues and organs, carbohydrate balance must be maintained at a given level. This drive for balance may in turn cause increased energy intake when consuming a diet high in fat and low in carbohydrate. If sustained over time, such an increase in energy intake cannot be detected by available methods, but may cause meaningful increases in body weight. The concept of metabolic flexibility and its impact on body weight regulation is also presented.

Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men.

AIMS: A high-fructose diet (HFrD) may play a role in the obesity and metabolic disorders epidemic. In rodents, HFrD leads to insulin resistance and ectopic lipid deposition. In healthy humans, a four-week HFrD alters lipid homoeostasis, but does not affect insulin sensitivity or intramyocellular lipids (IMCL). The aim of this study was to investigate whether fructose may induce early molecular changes in skeletal muscle prior to the development of whole-body insulin resistance. METHODS: Muscle biopsies were taken from five healthy men who had participated in a previous four-week HFrD study, during which insulin sensitivity (hyperinsulinaemic euglycaemic clamp), and intrahepatocellular lipids and IMCL were assessed before and after HFrD. The mRNA concentrations of 16 genes involved in lipid and carbohydrate metabolism were quantified before and after HFrD by real-time quantitative PCR. RESULTS: HFrD significantly (P<0.05) increased stearoyl-CoA desaturase-1 (SCD-1) (+50%). Glucose transporter-4 (GLUT-4) decreased by 27% and acetyl-CoA carboxylase-2 decreased by 48%. A trend toward decreased peroxisomal proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was observed (-26%, P=0.06). All other genes showed no significant changes. CONCLUSION: HFrD led to alterations of SCD-1, GLUT-4 and PGC-1alpha, which may be early markers of insulin resistance.

Psychosocial and behavioral pre-treatment predictors of weight loss outcomes.

OBJECTIVE: This study tested whether baseline behavioral and psychological variables predict weight and fat loss among overweight, non-obese individuals participating in a six-month calorie restriction trial. Participants (N=48) were randomly assigned to four groups, three of which included a calorie restriction program and one of which served as a healthy diet weight maintenance control. For the purposes of this study, data were analyzed only for participants assigned to the three calorie restriction groups (n=36). Ten psychological and behavioral measures were investigated through principal components factor analysis to examine whether these measures were assessing similar or distinct psychological and behavioral constructs. Based on the obtained six-factor solution, one measure from each domain was selected for inclusion in hierarchical regression analyses, which was used to test the relative importance of psychosocial and behavioral variables in predicting percent weight and fat loss over six months. After controlling for demographic and treatment variables, the behavioral and psychological measures of negative mood states, poor psychosocial functioning, and somatic symptoms were associated with less weight loss (R2=0.68, p<0.001) and fat loss (R2=0.65, p<0.001) over six months. Among overweight individuals, poor psychological adjustment, somatic symptoms, and negative mood states appear to form a psychosocial profile that is predictive of less weight and fat loss in calorie restriction programs.

Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories.

Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis.

Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that is known to decrease food intake and increase energy expenditure in ob/ob mice. In humans, variants in the OB gene have not been detected and very little is known about the action of leptin on food intake and energy expenditure, although circulating leptin concentrations are positively correlated to body fat stores. The purpose of this study was to assess the relationship between fasting plasma leptin concentrations and energy expenditure in 123 5-yr-old Pima Indian children (67 males/76 females). Body composition was assessed by isotopic water dilution (18O) whereas total energy expenditure (TEE) and resting metabolic rate (RMR) were measured using doubly labeled water and indirect calorimetry, respectively. The physical activity level was calculated as the ratio of TEE:RMR. Plasma leptin concentrations were positively correlated to percent body fat (r = 0.84, P < 0.0001), but were similar in boys and girls after adjusting for percent body fat. Most importantly, we found that, independent of the percentage of body fat, plasma leptin concentrations correlated with TEE (in absolute values, r = 0.37, P < 0.0001, or adjusted for body size r = 0.42; P < 0.0001) and with physical activity level (r = 0.26, P < 0.01), but not RMR. These results suggest that, as in animal models, leptin plays a role in energy expenditure in humans.