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Background/objectives: Energy expenditure measured under sedentary conditions predicts weight change but evidence that directly measured VO 2 max is associated with weight change is lacking. The aim of this study was to determine the associations of VO 2 max with measures of predominantly sedentary 24-h thermogenesis, and subsequent weight change., Subjects/methods: Three hundred fifty-seven individuals (162 females; 27 Blacks, 72 Caucasians, and 258 American Indians) had measures of body composition, resting metabolic rate (RMR), and intermittent treadmill run test for assessment of VO 2 max. On a separate day, 24-h energy expenditure (EE), diet-induced thermogenesis (DIT) expressed as "awake and fed" thermogenesis (AFT), sleeping metabolic rate (SMR), and spontaneous physical activity (SPA) were measured in a whole-room indirect calorimeter. Follow-up weight for 217 individuals was available (median follow-up time, 9.5 y; mean weight change, 12.4 ± 14.9 kg)., Results: After adjustment for fat free mass, fat mass, age, sex, and race, a higher VO 2 max was associated with a higher RMR (β = 68.2 kcal/day per L/min, P < 0.01) and 24-h EE (β = 62.2 kcal/day per L/min, P < 0.05) and including additional adjustment for energy intake higher AFT (β = 66.1 kcal/day per L/min, P = 0.01). Neither SMR (P > 0.2) nor SPA (P > 0.8) were associated with VO 2 max. VO 2 max at baseline did not predict follow-up weight after adjustment for baseline weight, follow-up time, sex, and race (P > 0.4)., Conclusion: VO 2 max is associated with measures of EE including 24-h EE, RMR and DIT implying a common mechanism regulating the energetics of skeletal muscle during exercise and thermogenesis. However, this did not translate to VO 2 max as a predictor of weight change., (Published by Elsevier Inc.)

Background/objectives: Energy expenditure (EE), as reflective of body energy demand, has been proposed to be the key driver of food intake, possibly influencing weight change in humans. Variation in this energy-sensing link (overeating relative to weight-maintaining energy requirements) may lead to weight gain over time., Subjects/methods: Sixty-one overweight otherwise healthy Native Americans (age: 34.0 ± 7.9 years, body fat: 39.7 ± 9.5%, 36 males) were admitted to our clinical research unit for measurements of body composition by dual-energy X-ray absorptiometry, and 24-h EE and respiratory quotient (RQ) in a whole-room indirect calorimeter during energy balance and weight stability. Following this, ad libitum food intake was assessed for three days using computerized vending machines. Body weight change under unrestricted free-living conditions was assessed at an outpatient follow-up visit (median follow-up time = 1.7 years)., Results: Total ad libitum food intake (3-day average) was positively associated with 24-h EE (r = 0.44, p < 0.001), RQ (r = 0.34, p = 0.007), and fat free mass (r = 0.38, p = 0.002). A relatively greater food intake after accounting for 24-h EE, but not for RQ (p = 0.30) or for fat free mass (p = 0.23) nor total food intake (p = 0.16), predicted weight gain at the outpatient follow-up visit (r = 0.26, p = 0.04), such that overeating 100 Kcal/d above the food intake predicted by 24-h EE at baseline was associated with an average weight gain of 0.22 Kg over the follow-up period (95% CI: 0.01 to 0.42 Kg). This was due to relatively greater dietary fat intake (r = 0.32, p = 0.01), but not carbohydrate (p = 0.27) or protein (p = 0.06) intake., Conclusion: The individual propensity to overeating, particularly fat, in excess of the weight-maintaining energy requirements can be assessed and predicts long-term weight gain, suggesting that variation in energy sensing may influence appetite by favoring overeating thus promoting obesity development., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Human sleep is generally consolidated into a single prolonged period, and its metabolic consequence is to impose an extended period of fasting. Changes in sleep stage and homeostatic sleep drive following sleep onset may affect sleeping metabolic rate through cross talk between the mechanisms controlling energy metabolism and sleep. The purpose of this study was to isolate the effects of sleep stage and time after sleep onset on sleeping metabolic rate., Methods: The sleeping metabolic rate of 29 healthy adults was measured using whole room indirect calorimetry, during which polysomnographic recording of sleep was performed. The effects of sleep stage and time after sleep onset on sleeping metabolic rate were evaluated using a semi-parametric regression analysis. A parametric analysis was used for the effect of sleep stage and a non-parametric analysis was used for the effect of time., Results: Energy expenditure differed significantly between sleep stages: wake after sleep onset (WASO)>stage 2, slow wave sleep (SWS), and REM; stage 1>stage 2 and SWS; and REM>SWS. Similarly, carbohydrate oxidation differed significantly between sleep stages: WASO > stage 2 and SWS; and stage 1>SWS. Energy expenditure and carbohydrate oxidation decreased during the first half of sleep followed by an increase during the second half of sleep., Conclusions: This study identified characteristic phenotypes in energy expenditure and carbohydrate oxidation indicating that sleeping metabolic rate differs between sleep stages., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is highly expressed in liver and oxidative tissues. PC-TP promotes hepatic glucose production during fasting and aggravates glucose intolerance in high fat fed mice. However, because PC-TP also suppresses thermogenesis in brown adipose tissue (BAT), its direct contribution to obesity-associated diabetes in mice remains unclear. Here we examined the effects of genetic PC-TP ablation on glucose homeostasis in leptin-deficient ob/ob mice, which exhibit both diabetes and altered thermoregulation., Animals/methods: Mice lacking both PC-TP and leptin (Pctp -/- ;ob/ob) were prepared by crossing Pctp -/- with ob/+ mice. Glucose homeostasis was assessed by standard assays, and energy expenditure was determined by indirect calorimetry using a comprehensive laboratory animal monitoring system, which also recorded physical activity and food intake. Body composition was determined by NMR and hepatic lipids by enzymatic assays. Core body temperature was measured using a rectal thermocouple probe., Results: Pctp -/- ;ob/ob mice demonstrated improved glucose homeostasis, as evidenced by markedly improved glucose and pyruvate tolerance tests, without changes in insulin tolerance. However, there were no differences in EE at any ambient temperature. There were also no effects of PC-TP expression on physical activity, food intake or core body temperature., Conclusions: Improved glucose tolerance in Pctp -/- ;ob/ob mice in the absence of increases in energy expenditure or core body temperature indicates a direct pathogenic role for PC-TP in diabetes in leptin deficient mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: For unknown reasons, interval training often reduces body weight more than energy-expenditure matched continuous training. We compared the acute effects of time-duration and oxygen-consumption matched interval- vs. continuous exercise on excess post-exercise oxygen consumption (EPOC), substrate oxidation rates and lipid metabolism in the hours following exercise in subjects with type 2 diabetes (T2D)., Methods: Following an overnight fast, ten T2D subjects (M/F: 7/3; age=60.3±2.3years; body mass index (BMI)=28.3±1.1kg/m(2)) completed three 60-min interventions in a counterbalanced, randomized order: 1) control (CON), 2) continuous walking (CW), 3) interval-walking (IW - repeated cycles of 3min of fast and 3min of slow walking). Indirect calorimetry was applied during each intervention and repeatedly for 30min per hour during the following 5h. A liquid mixed meal tolerance test (MMTT, 450kcal) was consumed by the subjects 45min after completion of the intervention with blood samples taken regularly., Results: Exercise interventions were successfully matched for total oxygen consumption (CW=1641±133mL/min; IW=1634±126mL/min, P>0.05). EPOC was higher after IW (8.4±1.3l) compared to CW (3.7±1.4l, P<0.05). Lipid oxidation rates were increased during the MMTT in IW (1.03±0.12mg/kg per min) and CW (0.87±0.04mg/kg per min) compared with CON (0.73±0.04mg/kg per min, P<0.01 and P<0.05, respectively), with no difference between IW and CW. Moreover, free fatty acids and glycerol concentrations, and glycerol kinetics were increased comparably during and after IW and CW compared to CON., Conclusions: Interval exercise results in greater EPOC than oxygen-consumption matched continuous exercise during a post-exercise MMTT in subjects with T2D, whereas effects on substrate oxidation and lipid metabolism are comparable., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We have previously reported that mice with neuron-specific LPL deficiency (NEXLPL-/-) become obese by 16weeks of age on chow. Moreover, these mice had reduced uptake of triglyceride (TG)-rich lipoprotein-derived fatty acids and lower levels of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) in the hypothalamus. Here, we asked whether increased dietary fat content or altered dietary composition could modulate obesity development in NEXLPL-/- mice. Male NEXLPL-/- mice and littermate controls (WT) were randomly assigned one of three synthetic diets; a high carbohydrate diet (HC, 10% fat), a high-fat diet (HF, 45% fat), or a HC diet supplemented with n-3 PUFAs (HCn-3, 10% fat, Lovaza, GSK®). After 42weeks of HC feeding, body weight and fat mass were increased in the NEXLPL-/- mice compared to WT. WT mice fed a HF diet displayed typical diet-induced obesity, but weight gain was only marginal in HF-fed NEXLPL-/- mice, with no significant difference in body composition. Dietary n-3 PUFA supplementation did not prevent obesity in NEXLPL-/- mice, but was associated with differential modifications in hypothalamic gene expression and PUFA concentration compared to WT mice. Our findings suggest that neuronal LPL is involved in the regulation of body weight and composition in response to either the change in quantity (HF feeding) or quality (n-3 PUFA-enriched) of dietary fat. The precise role of LPL in lipid sensing in the brain requires further investigation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze., Design: Randomized, open, parallel-group trial., Methods: Healthy non-selected participants were randomized to achieve cold-exposure 1hour/day, or to avoid any sense of feeling cold, for 6weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI)., Results: Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841±199 kCal/24h to 1795±213 kCal/24h, p=0.047 cold-activated MR from 1900±150 kCal/24h to 1793±215 kCal/24h, p=0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p=0.052). The difference between MR changes by the interventions between groups was statistically significant (p=0.008 at room temperature, p=0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported ≥8days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175±0.015l to 0.0216±0.014l, p=0.049)., Conclusions: We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8week old male mice and again at 25weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The exact mechanism for different propensities to obesity when consuming a high-fat diet (HFD) is largely unknown. Thyroid hormone (TH) is an important modulator of energy homeostasis and body weight., Objective: The present study aimed to find the potential mechanisms of TH in the development of obesity-prone (OP) and obesity-resistant (OR) mice after short-term and long-term HFD feeding., Methods: C57Bl/6 male mice were randomly divided into two groups: a low-fat diet (LFD) group and an HFD group. In the 7th week, HFD-fed mice were classified as OP or OR according to upper and lower tertiles of body weight. Half of the mice were sacrificed at this time point and the remaining mice were kept on feeding and sacrificed in the 27th week. Indirect calorimetry was performed. At harvest, serum was used for ELISA assays and oxidative stress biomarkers determination. Tissues were dissected for deiodinases activity and relative mRNA expression determination, as well as antioxidant capacity evaluation., Results: In the 7th week, OP mice showed a significant body weight gain, decreased energy expenditure (EE), normal circulating TH levels, and activated HPT axis, whereas OR mice had normal body weight and maintained T(3) levels only through enhancing hepatic D1 activity. In the 27th week, OR mice gained more body weight than LFD mice accompanied by an activation of HPT axis and decreased hepatic deiodination. Genes involved in TH production were down-regulated in OP mice and up-regulated in OR mice. Changes in deiodinases activity and thyroid function were related with redox status in specific tissues. Furthermore, OP mice had more serious hepatic steatosis than OR mice, with up-regulation of T(3) target genes (e.g. Srebp1c, Acc1, Fasn) involved in lipid synthesis and down-regulation of Pgc1α, Cyp7a1 and Cpt1α., Conclusions: HPT axis function and deiodinases activity might be involved in different propensities to obesity and the ability of OR mice to resist obesity was limited., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Obesity is a result of chronic overconsumption of calories relative to the amount of energy expended. While fat free mass can account for ~80% of the variance in energy expenditure, there is still considerable variability in energy requirements between individuals that cannot be explained. We hypothesized that responsiveness to the recently discovered myokine, irisin, which has been touted to increase energy expenditure via activation of brown adipocytes in rodents and possibly humans, may explain some of the variability in energy expenditure., Materials/methods: Post-menopausal women (n=17) spent 24-h in a whole room indirect calorimeter. During the study day, subjects remained sedentary and consumed meals tailored to their energy requirements. Plasma irisin, leptin and adiponectin were measured in samples taken from each subject., Results: Our results suggest that in general, irisin levels do not correlate with 24-h energy expenditure, however, for a subpopulation irisin levels and energy expenditure are highly correlative., Conclusion: Irisin may help explain some of the observed variability in individual energy requirements that cannot be accounted for by fat free mass. Therefore, interventions designed to increase irisin action may prove to be promising avenues for the treatment of obesity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate the effects of a single session of sprint interval training (SIT) and a single extended sprint (ES), matched for total work, on metabolic health biomarkers., Methods: Ten overweight/obese men aged 26.9±6.2years participated. Following a pre-trial incremental exercise test and SIT familiarization, each participant undertook three 2-day trials in randomized order. On Day 1 participants either undertook no exercise (CON), four maximal 30-s sprints, with 4.5min recovery between each (SIT), or a single maximal extended sprint (ES) matched with SIT for work done. On Day 2, participants had a fasting blood sample taken, undertook an oral glucose tolerance test to determine insulin sensitivity index (ISI), and had blood pressure measured., Results: Total work done during exercise did not differ between SIT and ES (61.7±2.9 vs. 61.3±2.8kJ; p=0.741). Mean power was higher in SIT than ES (518±21 vs. 306±16W, p<0.0005), resulting in a shorter high-intensity exercise duration in SIT (120±0 vs. 198±10s, p<0.0005). ISI was 44.6% higher following ES than CON (9.4±2.1 vs. 6.5±1.3; p=0.022), but did not differ significantly between SIT and CON (6.6±0.9 vs. 6.5±1.3; p=0.208). However, on the day following exercise fat oxidation in the fasted state was increased by 63% and 38%, compared to CON, in SIT and ES, respectively (p<0.05 for both), with a concomitant reduction in carbohydrate oxidation (p<0.05)., Conclusion: A single ES, which may represent a more time-efficient alternative to SIT, can increase insulin sensitivity and increase fat oxidation in overweight overweight/obese sedentary men., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Low levels of daily energy expenditure (insufficient physical activity and increased sedentary time) have been associated with adverse health outcomes in young people. The Multimedia Activity Recall for Children and Adolescents (MARCA) is a computerized, self-report, use-of-time tool that can assess daily energy expenditure. The study aim was to validate the MARCA for the estimation of energy expenditure in young people, using the criterion standard doubly labeled water., Materials/methods: Over a 15 day assessment period, 32 participants (10-18 years) completed the MARCA and underwent a doubly labeled water protocol. Indirect calorimetry was used to assess resting metabolic rate. Total daily energy expenditure (TEE) and activity-related energy expenditure (AEE) were estimated from both the MARCA and doubly labeled water. Association and agreement between methods for TEE and AEE were assessed using Spearman correlations and Bland-Altman plots, respectively., Results: Compared to doubly labeled water, the MARCA over-estimated TEE by an average of 50 kcal/day (limits of agreement -1 589 to 1 490 kcal/day) and under-estimated AEE 105 kcal/day (limits of agreement -1 404 to 1 614 kcal/day). The MARCA showed strong correlation with doubly labeled water for TEE (rho=0.70, p<0.0001) and moderate correlation for AEE (rho=0.56, p=0.0009)., Conclusions: Overall, the MARCA indicated moderate validity for the assessment of daily TEE and AEE. The wide limits of agreement indicate the MARCA has greater utility for group-level rather than individual-level estimates., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The fatty acid profile of dietary fats may contribute to its channelling toward oxidation versus storage, influencing energy and weight balance. Our objective was to compare the effects of diets enriched with high-oleic canola oil (HOCO), alone or blended with flaxseed oil (FXCO), on energy expenditure, substrate utilization, and body composition versus a typical Western diet (WD)., Materials/methods: Using a randomized crossover design, 34 hypercholesterolemic subjects (n=22 females) consumed 3 controlled diets for 28 days containing ~49% energy from carbohydrate, 14% energy from protein, and 37% energy from fat, of which 70% of fat was provided by HOCO rich in oleic acid, FXCO rich in alpha-linolenic acid, or WD rich in saturated fat. Indirect calorimetry measured energy expenditure and substrate oxidation. Body composition was analyzed by dual-energy x-ray absorptiometry., Result: After 28 days, resting and postprandial energy expenditure and substrate oxidation were not different after consumption of the HOCO or FXCO diets compared with a typical Western diet. No significant changes in body composition measures were observed between diets. However, the android-to-gynoid ratio tended to increase (P=.055) after the FXCO diet compared with the HOCO diet., Conclusions: The data suggest that substituting a typical Western dietary fatty acid profile with HOCO or FXCO does not significantly modulate energy expenditure, substrate oxidation or body composition in hypercholesterolemic males and females., (Copyright © 2012 Elsevier Inc. All rights reserved.)

HIV-associated dyslipemic lipodystrophy (HADL) is a heterogeneous syndrome of fat redistribution, hypertriglyceridemia, and insulin resistance, associated with markedly accelerated rates of lipolysis, intraadipocyte and intrahepatic reesterification, and very low-density lipoprotein-triglyceride synthesis and release. The objective of the study was to determine if rosiglitazone can ameliorate these lipid kinetic defects in patients with HADL. Infusions of [(13)C(1)]palmitate and [(2)H(5)]glycerol were used to measure total and net lipolysis, adipocyte and hepatic reesterification, and plasma free fatty acid (FFA) oxidation in 9 men with HADL, before and after 3 months of treatment with rosiglitazone (8 mg/d). Rosiglitazone treatment significantly increased both total lipolysis (R(a) FFA(total) from 3.37 ± 0.40 to 4.57 ± 0.68 mmol FFA per kilogram fat per hour, P < .05) and adipocyte reesterification (1.25 ± 0.35 to 2.43 ± 0.65 mmol FFA per kilogram fat per hour, P < .05). However, there was no change in net lipolysis (R(a) FFA(net) 2.47 ± 0.43 to 2.42 ± 0.37 mmol FFA per kilogram fat per hour), plasma FFA oxidation (0.30 ± 0.046 to 0.32 ± 0.04 mmol FFA per kilogram lean body mass per hour), or FFA flux available for hepatic reesterification (0.59 ± 0.07 to 0.56 ± 0.10 mmol FFA per kilogram fat per hour). There were significant decreases in fasting plasma insulin concentrations and insulin resistance, but not in fasting plasma lipid or glucose concentrations. There was a significant decrease in waist to hip ratio (0.98 ± 0.02 to 0.95 ± 0.02, P < .05) consistent with a significant increase in hip circumference (0.93 ± 0.02 to 0.95 ± 0.02 m, P < .05), without change in waist circumference. Rosiglitazone significantly increased adipocyte reesterification and improved insulin sensitivity, but the potential benefit of these changes was compromised by increase in total lipolysis. Combining rosiglitazone with agents designed to blunt lipolysis could expand depleted peripheral adipose depots in patients with HIV lipodystrophy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

It has been demonstrated that the polymorphism 385 C/A of fatty acid amide hydrolase was associated with obesity. We decided to investigate the role of a polymorphism (cDNA 385 C->A) on insulin resistance and weight loss secondary to a low-fat vs a low-carbohydrate diet. A population of 248 patients with obesity was analyzed. Basal measurements were performed, and values were compared to those at the end of a 3-month period in which subjects received either diet I (low fat) or diet II (low carbohydrate). One hundred seventy-eight patients (71.8%) had the genotype C358C (wild-type group), and 70 (28.2%) patients had the genotype C358A (62 patients, 25%) or A358A (8 patients, 3.2%) (mutant-type group). With diet I, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in the wild-type and mutant-type groups. With diet II, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased in both genotypes. With diet I, leptin, glucose, total cholesterol, triglyceride, insulin, and homeostasis model assessment for insulin sensitivity (HOMA) decreased in the wild-type group. In the mutant-type group, only cholesterol decreased in a significant way. With diet II, leptin, interleukin-6, glucose, total cholesterol, low-density lipoprotein cholesterol, insulin, HOMA, and C-reactive protein decreased in the wild-type genotype. The allele A358 of fatty acid amide hydrolase was associated with a lack of improvement on glucose insulin, HOMA, and leptin levels in both diets after weight loss., (Copyright 2010 Elsevier Inc. All rights reserved.)

Skeletal muscle mitochondrial dysfunction is associated with aging and diabetes, which decreases respiratory capacity and increases reactive oxygen species. Lipoic acid (LA) possesses antioxidative and antidiabetic properties. Metabolic action of LA is mediated by activation of adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor that can regulate peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis. We hypothesized that LA improves energy metabolism and mitochondrial biogenesis by enhancing AMPK-PGC-1alpha signaling in the skeletal muscle of aged mice. C57BL/6 mice (24 months old, male) were supplemented with or without alpha-LA (0.75% in drinking water) for 1 month. In addition, metabolic action and cellular signaling of LA were studied in cultured mouse myoblastoma C2C12 cells. Lipoic acid supplementation improved body composition, glucose tolerance, and energy expenditure in the aged mice. Lipoic acid increased skeletal muscle mitochondrial biogenesis with increased phosphorylation of AMPK and messenger RNA expression of PGC-1alpha and glucose transporter-4. Besides body fat mass, LA decreased lean mass and attenuated phosphorylation of mammalian target of rapamycin (mTOR) signaling in the skeletal muscle. In cultured C2C12 cells, LA increased glucose uptake and palmitate beta-oxidation, but decreased protein synthesis, which was associated with increased phosphorylation of AMPK and expression of PGC-1alpha and glucose transporter-4, and attenuated phosphorylation of mTOR and p70S6 kinase. We conclude that LA improves skeletal muscle energy metabolism in the aged mouse possibly through enhancing AMPK-PGC-1alpha-mediated mitochondrial biogenesis and function. Moreover, LA increases lean mass loss possibly by suppressing protein synthesis in the skeletal muscle by down-regulating the mTOR signaling pathway. Thus, LA may be a promising supplement for treatment of obesity and/or insulin resistance in older patients.

Fat oxidation (FO) is optimized during low- to moderate-intensity exercise in lean and obese subjects, whereas high-intensity exercise induces preferential FO during the recovery period. After food intake during the postexercise period, it is unknown if FO differs according to the intensity exercise in overweight subjects. Fat oxidation was thus evaluated in overweight men after low- and high-intensity exercise during the recovery period before and after food intake as well as during a control session. Ten healthy, sedentary, overweight men (age, 27.9 +/- 5.6 years; body mass index, 27.8 +/- 1.3 kg m(-2); maximal oxygen consumption, 37 +/- 3.9 mL min(-1) kg(-1)) exercised on a cycloergometer (energy expenditure = 300 kcal) at 35% (E35) or 70% (E70) maximal oxygen consumption or rested (Cont). The subjects were fed 30 minutes after the exercise with 300 kcal (1256 kJ) more energy in the exercise sessions than in the Cont session. Respiratory quotient and FO were calculated by indirect calorimetry. Blood samples were analyzed to measure plasma glycerol, nonesterified fatty acid, glucose, and insulin. During exercise, mean respiratory quotient was lower (P < .05) and FO was higher (P < .01) in the E35 than in the E70 session (FO [in mg min(-1)]: E35 = 290 +/- 12, E70 = 256 +/- 38, and Cont = 131 +/- 7). Conversely, FO was higher in the E70 than in both the E35 session and the Cont session during the immediate recovery as well as during the postprandial recovery period (P = .005 for all; FO from the end of the exercise to the end of the session [in grams]: E70 = 45.7 +/- 8.9, E35 = 38.2 +/- 6.8, and Cont = 36.0 +/- 4.3). Blood parameters did not differ between the 3 sessions but changed according to the absorption of the nutrients. In overweight subjects, high-intensity exercise increased FO during the postexercise period even after food intake compared with the low-intensity exercise and the control session., (Copyright 2010 Elsevier Inc. All rights reserved.)

The fatty acid composition of high-fat diets is known to influence the magnitude of postprandial events that increase the risk of metabolic syndrome. These variations in magnitude may be directly ascribed to differences in the channeling of lipids toward oxidation or storage. A study was designed to compare the effects of 4 dietary fats on postprandial energy expenditure and on some risk factors of the metabolic syndrome. To avoid usual confounding factors due to simultaneous variations in chain length and double-bounds number of fatty acids, dietary fats were chosen to provide mainly 18-carbon fatty acids with 0 (stearic acid [SA]), 1 (oleic acid [OA]), 2 (linoleic acid [LA]), or 3 (alpha-linolenic acid [ALA]) double bounds. They were given as single high-fat test meals to 4 different groups of male rats. The resting metabolic rate and the lipid and carbohydrate oxidation were measured from oxygen consumption and carbon dioxide production using indirect calorimetry 2 hours before and 6.5 hours after the test meal. Plasma glucose, triglyceride, and chylomicron concentrations were determined at 0, 1.5, and 4 hours after the test meal. Postprandial concentration of glucose and triglyceride did not vary with the nature of the test meals, whereas that of chylomicrons was the highest after the LA test meal and the lowest after the SA test meal. Postprandial increase in resting metabolic rate was the highest after the LA and OA test meals, and the lowest after the SA and ALA test meals. Compared with the 3 other diets, the ALA test meal enhanced lipid oxidation and decreased glucose oxidation during the early postprandial period (0.25-3.25 hours). This suggests that stearic acid may not induce all the adverse effects classically described for other saturated fatty acids and that alpha-linolenic acid may beneficially influence energy partitioning, especially during the early postprandial state., (Copyright 2010 Elsevier Inc. All rights reserved.)

Fatty acids (FA) can impair glucose metabolism to a varying degree depending on time of exposure and also of type of FA. Here we tested for acute effects of marine n-3 FA on insulin sensitivity, insulin secretion, energy metabolism, and oxidative stress. This was a randomized, double-blind, crossover study in 11 subjects with type 2 diabetes mellitus. A 4-hour lipid infusion (Intralipid [Fresenius Kabi, Halden, Norway], total of 384 mL) was compared with a similar lipid infusion partly replaced by Omegaven (Fresenius Kabi) that contributed a median of 0.1 g fish oil per kilogram body weight, amounting to 0.04 g/kg of marine n-3 FA. Insulin sensitivity was assessed by isoglycemic hyperinsulinemic clamps; insulin secretion (measured after the clamps), by C-peptide glucagon tests; and energy metabolism, by indirect calorimetry. Infusion of Omegaven increased the proportion of n-3 FA in plasma nonesterified fatty acids (NEFA) compared with Intralipid alone (20:5n-3: median, 1.5% [interquartile range, 0.6%] vs -0.2% [0.2%], P = .001; 22:6n-3: 0.8% [0.4%] vs -0.7% [0.2%], P = .001). However, glucose utilization was not affected; neither was insulin secretion or total energy production (P = .966, .210, and .423, respectively, for the differences between the lipid clamps). Omegaven tended to lower oxidation of fat (P = .062) compared with Intralipid only, correlating with the rise in individual n-3 NEFA (r = 0.627, P = .039). The effects of clamping on phospholipid FA composition, leptin, adiponectin, or F(2)-isoprostane concentrations were not affected by Omegaven. Enrichment of NEFA with n-3 FA during a 4-hour infusion of Intralipid failed to affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus.

The present study aimed to examine the effects of a prior 1-hour continuous exercise bout (CONT) at an intensity (Fat(max)) that elicits the maximal fat oxidation (MFO) on the fat oxidation kinetics during a subsequent submaximal incremental test (IncrC). Twenty moderately trained subjects (9 men and 11 women) performed a graded test on a treadmill (Incr), with 3-minute stages and 1-km.h(-1) increments. Fat oxidation was measured using indirect calorimetry and plotted as a function of exercise intensity. A mathematical model (SIN) including 3 independent variables (dilatation, symmetry, and translation) was used to characterize the shape of fat oxidation kinetics and to determine Fat(max) and MFO. On a second visit, the subjects performed CONT at Fat(max) followed by IncrC. After CONT performed at 57% +/- 3% (means +/- SE) maximal oxygen uptake (Vo(2max)), the respiratory exchange ratio during IncrC was lower at every stage compared with Incr (P < .05). Fat(max) (56.4% +/- 2.3% vs 51.5% +/- 2.4% Vo(2max), P = .013), MFO (0.50 +/- 0.03 vs 0.40 +/- 0.03 g.min(-1), P < .001), and fat oxidation rates from 35% to 70% Vo(2max) (P < .05) were significantly greater during IncrC compared with Incr. However, dilatation and translation were not significantly different (P > .05), whereas symmetry tended to be greater in IncrC (P = .096). This study showed that the prior 1-hour continuous moderate-intensity exercise bout increased Fat(max), MFO, and fat oxidation rates over a wide range of intensities during the postexercise incremental test. Moreover, the shape of the postexercise fat oxidation kinetics tended to have a rightward asymmetry.

Metabolic flexibility is the ability to transition between fat oxidation (fasting state) and glucose oxidation (fed state). We hypothesized that adipose tissue inflammation and lipid metabolism contribute to sexual dimorphism in metabolic flexibility. Respiratory quotient (DeltaRQ, metabolic flexibility) and nonesterified fatty acids (NEFAs) before and during euglycemic-hyperinsulinemic clamp were measured in healthy young women (n = 22) and men (n = 56). Adiponectin levels were measured in plasma. Abdominal subcutaneous adipose tissue gene expression was measured by quantitative reverse transcriptase polymerase chain reaction. As compared with men, women had higher DeltaRQ (0.14 +/- 0.04 vs 0.09 +/- 0.04, P < .01). Fasting RQ and fat cell size were not different between sexes. As compared with men, women had lower insulin-suppressed NEFAs (P < .05); greater adiponectin levels; and higher expression of adipogenesis, fatty acid storage, and oxidation genes (PPARgamma2, PCK1, SCD1, and PPARalpha; P < .05). There were no sex differences in messenger RNA of macrophage markers or chemokines. Stepwise regression analysis revealed that the only adipose tissue characteristics that influenced metabolic flexibility in women were SCD1 and PCK1 messenger RNA (model R(2) = 0.49, P < .05); in men, these were serum adiponectin and insulin-suppressed NEFAs (model R(2) = 0.34, P < .05). Healthy young women are more metabolically flexible than men, driven by an increase in insulin-stimulated glucose oxidation rather than differences in fasting fat oxidation. Women have greater capacity for insulin suppression of NEFAs despite similar chemokine and macrophage content in adipose tissue. Combined, these results provide evidence for a role of adipose tissue characteristics in the sexual dimorphism of metabolic flexibility.

The purpose of this study was to examine metabolic rate and substrate oxidation during sleep in relation to time of sleep and sleep stage. Twelve male subjects free from sleep-disordered breathing slept for 469 +/- 8.7 (mean +/- SE) minutes until natural awakening in a whole-body indirect calorimeter, and polysomnographic documentation of sleep was recorded. Energy expenditure decreased during the first half of the night, reached a nadir (a 35% decrease), and remained relatively stable until awakening. Similarly, fat oxidation decreased from the onset of sleep. On the other hand, carbohydrate oxidation showed no remarkable changes from the onset of sleep but began to increase before awakening. Because distribution of sleep stages is not uniform throughout the night, with rapid-eye-movement (REM) sleep tending to appear later in the sleep, effect of sleep stage on energy metabolism was isolated by analysis of covariance with time as a covariate. Subsequent comparison of metabolic rate by 1-way analysis of variance with Bonferroni post hoc analysis revealed that energy expenditure during REM sleep was significantly greater than that during sleep stages 2 and 3/4 (stage 2, 25.248 +/- 0.961; stage 3/4, 24.825 +/- 0.935; REM, 25.712 +/- 0.928 kcal kg(-1) fat-free mass d(-1)). Carbohydrate oxidation during REM sleep was significantly greater than that during sleep stage 3/4 (stage 3/4, 12.229 +/- 1.071; REM, 13.986 +/- 1.291 kcal kg(-1) fat-free mass d(-1)). Respiration quotient was statistically different among sleep stages, but Bonferroni post hoc analysis failed to identify significant differences (stage 2, 0.850 +/- 0.010; stage 3/4, 0.846 +/- 0.011; REM, 0.861 +/- 0.013). The increases in energy expenditure and carbohydrate oxidation during REM sleep are consistent with a notion that changes in energy metabolism in brain are manifested as small fluctuations in whole-body energy metabolism during sleep.

The purpose of this study was to evaluate the relationship of respiratory quotient (RQ), a surrogate marker of substrate oxidation, as well as body composition and dietary intake to resting energy expenditure (REE) among HIV-infected patients in the current era of highly active antiretroviral therapy and among non-HIV-infected control subjects. Resting energy expenditure is increased in HIV-infected patients; but little is known regarding the potential contribution of altered substrate metabolism, body composition, and dietary intake to increased energy expenditure in this population. Respiratory quotient, REE, body composition, and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls who were evaluated for metabolic studies between 1998 and 2005. Respiratory quotient was lower (0.83 +/- 0.00 vs 0.85 +/- 0.01, P = .005), whereas REE adjusted for fat-free mass (FFM) was higher (31.8 +/- 0.3 vs 29.8 +/- 0.3 kcal/[d kg], P < or = .0001), in HIV-infected compared with control subjects. In multivariate modeling among HIV-infected patients, including age, sex, and parameters of immune function, FFM (beta = 24.811334, P < .0001), visceral adiposity (beta = .7182746, P = .008), and total body fat (beta = 8.0506839, P = .041) were positively associated with REE, whereas RQ was negatively associated with REE (beta = -528.4808, P = .024). Overall r(2) was equal to 0.705 and P was less than .0001 for the model. In control subjects, by contrast, only visceral adiposity (beta = 1.0612073, P = .004), total body fat (beta = 15.805547, P = .010), and FFM (beta = 22.613005, P < .0001) were significant predictors of REE; and there was no relationship with RQ. Overall r(2) was equal to 0.825 and P was less than .0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared with control subjects.

Persistent suppression of hyperinsulinemia in genetically obese (fa/fa) Zucker rats by diazoxide (DZ) reduces food intake and weight gain; improves insulin sensitivity, glycemic control, and lipid profile; and enhances beta(3)-adrenergic function and lipolysis in adipose tissue. The aim of this study was to elucidate the effects of DZ on basal metabolic rate (BMR), fat oxidation, and adrenergic function of lean and obese Zucker rats. Diazoxide (150 mg/kg/d) or vehicle (control) was administered for 4 weeks in 7-week-old obese and lean Zucker rats (n = 8-9 per subgroup). Animals underwent indirect calorimetry, body composition analysis, and determination of uncoupling proteins (UCPs) messenger RNA (mRNA) in brown and white adipose tissues (BAT and WAT) and skeletal muscle (SM), beta(3)-adrenergic receptor (AR) mRNA in BAT and WAT, beta(2)-AR in SM as well as WAT, and SM adenylate cyclase (AC) activity at the completion of study. Diazoxide treatment decreased food intake, weight gain, and body fat in obese rats (P < .01). Although DZ treatment lowered fasting plasma glucose, insulin, leptin, adiponectin, and lipids in obese rats (P < .01), it increased adiponectin-leptin ratio (P < .01). Plasma adiponectin-leptin ratio was inversely correlated with fat mass in obese and lean rats (r = -0.86, P < .0001). Diazoxide treatment resulted in higher BMR and fat oxidation rate in obese compared with control animals (P < .01), without any effect in lean animals. Furthermore, plasma adiponectin was inversely correlated with BMR (-0.56, P < .001) and lipid oxidation rate (-0.61, P < .0005) and was positively correlated with nonprotein respiratory quotient (r = 0.41, P < .01) in obese and lean rats. This was associated with increased beta(3)-AR mRNA expression in BAT and WAT (P < .01), UCP-1 and UCP-3 in BAT and AC activity in WAT (P < .02), and AC activity in SM of DZ obese rats compared with controls (P < .01), without significant change in SM beta(2)-AR mRNA expressions. Diazoxide attenuation of hyperinsulinemia decreased the rate of weight gain but enhanced insulin sensitivity, BMR, and fat oxidation in obese rats. This was associated with increased receptor- and non-receptor-mediated adrenergic function in adipose and muscle tissues in obese rats, respectively. These metabolic changes in obese Zucker rats suggest that antiobesity effects of DZ appear to be not only through its anorectic effect, modification of disturbed insulin metabolism, and inhibition of lipogenesis, but also due to augmentation of adrenergic function, energy expenditure, and fat utilization.

Peptide YY (PYY) and ghrelin have been associated with the regulation of energy balance. The objectives of this study were to determine whether total ghrelin and PYY after a standardized meal predict appetite scores and ad libitum energy intake (EI) and to examine the relationship between total ghrelin and PYY and postprandial energy expenditure (PEE). Twenty-five premenopausal women (age, 50.4 +/- 2.0 years; body mass index, 23.5 +/- 2.2 kg/m(2)) were studied. Total PYY, total ghrelin (enzyme-linked immunosorbent assay), EE (indirect calorimetry), and appetite scores (visual analogue scales) were measured fasting and every 30 minute for 3 hours after the ingestion of a standardized breakfast. Ad libitum EI was measured at lunch with a buffet-type meal. Peptide YY increased (P < .001) and total ghrelin decreased (P < .001) after breakfast. Significant changes in EE (P < .001) and appetite scores (P < .001) were noted postprandially. Appetite scores were consistently associated with ad libitum EI at lunch (r = -0.51 to 0.40, P < .05), whereas no association between EI and prelunch total ghrelin and PYY was observed. Finally, partial correlation analyses revealed that total PYY was a significant independent correlate of PEE at 60, 90, 120, and 150 minutes (r = 0.37-0.51, P

Basal fat oxidation decreases with age. In obesity, it is not known whether this age-related process occurs independently of changes in body composition and insulin sensitivity. Therefore, body composition, resting energy expenditure, basal substrate oxidation, and maximal oxygen consumption (VO(2)max) were measured in 10 older (age, 60 +/- 4 years; mean +/- SEM) and 10 younger (age, 35 +/- 4 years) body mass index-matched, obese, normal glucose-tolerant individuals. Fasting blood samples were also collected. Older subjects had slightly elevated fat mass (32.2 +/- 7.1 vs 36.5 +/- 6.7 kg, P = .16); however, waist circumference was not different between groups (104.3 +/- 10.3 vs 102.1 +/- 12.6 cm, P = .65). Basal fat oxidation was 22% lower (1.42 +/- 0.14 vs 1.17 +/- 0.22 mg/kg fat-free mass per minute, P = .03) in older subjects. The VO(2)max was also decreased in older individuals (44.6 +/- 7.1 vs 38.3 +/- 6.0 mL/kg fat-free mass per minute, P = .03); but insulin sensitivity, lipemia, and leptinemia were not different between groups (P > .05). Fat oxidation was most related to age (r = -0.61, P = .003) and VO(2)max (r = 0.52, P = .01). These data suggest that aging per se is responsible for reduced basal fat oxidation and maximal oxidative capacity in older obese individuals, independent of changes in insulin resistance, body mass, and abdominal fat. This indicates that age, in addition to obesity, is an independent risk factor for weight gain and for the metabolic complications of elevated body fat.

The study aimed to analyze the effects of a short-term very low-calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese nondiabetic and type 2 diabetic subjects. Seven untreated type 2 diabetic and 5 obese nondiabetic individuals were studied before and after a 6-day VLCD using proton magnetic resonance spectroscopy to quantify IMCL, dual-energy x-ray absorptiometry to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. In both groups, decrements in total body fat mass and body mass index were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared with baseline values in nondiabetic subjects (56% decrease) and type 2 diabetic subjects (40% decrease) (P < .05), and this was accompanied by an overall 9.3% increase in maximally stimulated glucose disposal rate (P < .01). Intramyocellular lipid was significantly correlated with insulin sensitivity (r = -0.69, P < .01) and waist circumference (r = 0.72 and 0.83, baseline and postdiet, respectively; both P < .01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as body mass index, percentage of body fat, or total body fat (P = not significant). In conclusion, short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in nondiabetic and type 2 diabetic subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL both in nondiabetic and type 2 diabetic subjects in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than to body fat per se.

Previous studies have linked overweight to lower milk and calcium consumption and have proposed a role of milk consumption on energy expenditure (EE). The goal of this study was to compare EE and food intake after a meal of either mixed-nutrient or single-nutrient beverage and examine whether supplementation with that beverage for 1 week will impact EE. This was a randomized, controlled crossover study testing the effect of 2 beverages, milk or fruit-flavored beverage, before and after a supplementation period of 1 week on EE. Food intake at a meal after a snack intake of each beverage was assessed at the end of each measurement period. Ten children, aged 9 to 10 years, participated in all of the testing sessions in the study. There was a significant beverage by testing day interaction on daily EE and thermic effect of food (TEF), whereby EE was greater with milk consumption relative to the fruit-flavored beverage on day 8 (P = .0014) and with fruit-flavored beverage consumption on day 1 vs day 8 (P = .01). Similarly, the TEF was greater with milk compared with fruit-flavored beverage consumption on day 8 (P = .0007) and with fruit-flavored beverage consumption on day 1 relative to day 8 (P = .0097). The TEF declined more rapidly during 6 hours after a fruit-flavored beverage than a milk meal (P = .0018). Food intake did not differ after snack consumption of each beverage before and after milk and fruit-flavored beverage supplementation periods. Over the longer term, consumption of milk beverages may have more favorable effects on energy balance in children than consumption of fruit-flavored beverages.

Although capable of inducing an anabolic state after surgery, parenteral nutrition, including glucose, leads to hyperglycemia. Even moderate increases in blood glucose are associated with poor surgical outcome. We examined the hypothesis that amino acids, in the absence of glucose supply, spare protein while preventing hyperglycemia. In this prospective study, 14 patients with colonic cancer were randomly assigned to undergo a 6-hour stable isotope infusion study (3 hours of fasting followed by 3-hour infusions of amino acids, Travasol [Baxter, Montreal, Canada] 10% at 0.02 mL.kg(-1).min(-1), with or without glucose at 4 mg.kg(-1).min(-1)) on the second day after colorectal surgery. Protein breakdown, protein oxidation, protein balance, and glucose production were assessed by stable isotope tracer kinetics using l-[1-(13)C]leucine and [6,6-(2)H2]glucose. Circulating concentrations of glucose, cortisol, insulin, and glucagon were determined. The administration of amino acids increased protein balance from -16+/-4 micromol.kg(-1).h(-1) in the fasted state to 16+/-3 micromol.kg(-1).h(-1). Combined infusion of amino acids and glucose increased protein balance from -17+/-7 to 7+/-5 micromol.kg(-1).h(-1). The increase in protein balance during nutrition was comparable in the 2 groups (P=.07). Combined administration of amino acids and glucose decreased endogenous glucose production (P=.001) and stimulated insulin secretion (P=.001) to a greater extent than the administration of amino acids alone. Hyperglycemia (blood glucose, 10.1+/-1.9 micromol/L) occurred only in the presence of glucose infusion. In summary, excluding glucose from a short-term feeding protocol does not diminish the protein-sparing effect of amino acids and avoids hyperglycemia.

We have previously shown that resting energy expenditure (REE) is increased in patients with HIV lipodystrophy. This hypermetabolism could be the result of an inadequate storage capacity for lipid fuel secondary to atrophy of the subcutaneous adipose tissue depot. Therefore, energy restriction may be able to alleviate this hypermetabolism. To test this hypothesis, we measured REE in HIV-infected patients with lipodystrophy and hypermetabolism and in HIV-infected and healthy controls. Measurements were taken during the overnight fasted state after 3 days on a eu-energetic diet and again after 3 days on a diet of similar composition but reduced in energy by 50%. After 3 days of eu-energetic feeding, REE was significantly higher in HIV-infected patients with lipodystrophy compared with healthy controls (139.5 +/- 1.3 vs 117.2 +/- 1.3 kJ/kg lean body mass, P < .001) and tended to be higher compared with HIV-infected subjects without lipodystrophy (139.5 +/- 13 vs 127.3 +/- 1.4 kJ/kg lean body mass, P = .06). Furthermore, energy restriction caused a significant decline in REE in patients with HIV lipodystrophy (P < .001). This dietary manipulation did not lead to a significant reduction in REE in either HIV-infected or healthy controls. This suggests that energy intake and REE may be uniquely coupled in patients with lipodystrophy as a means to dissipate energy that cannot be stored in a normal manner. A better understanding of this coupling would have important implications for weight regulation in general.

Critical illness is characterized by a hypermetabolic state associated with increased mortality, which is partly ascribed to the occurrence of hyperglycemia caused by enhanced endogenous glucose production and insulin resistance (IR). Insulin resistance is well described in patients after surgery and trauma. However, it is less clearly quantified in critically ill medical patients. In this clinical cohort study, IR (M value) was quantified in 40 critically ill medical patients and 25 matched, healthy controls by isoglycemic hyperinsulinemic clamps after an overnight fast on the day after admission to a medical intensive care unit. Energy and substrate metabolism were measured by using indirect calorimetry in the patients before and during the clamp. The severity of illness was assessed by the acute physiology and chronic health evaluation (APACHE) III score. M values of critically ill medical patients were significantly lower compared with healthy controls (2.29 +/- 1.0 and 7.6 +/- 2.9 mg/kg per minute, respectively; P < .001) and were closely related to APACHE III scores (r = -0.43, P < .01), body mass index (r = -0.41, P < .01), and resting energy expenditure (r = 0.40, P < .05). The M value was not associated with age, basal glucose concentrations, and respiratory quotient, and it did not differ among patients with various admission diagnoses. In conclusion, insulin sensitivity was found to be reduced by 70% in critically ill medical patients. The severity of IR was associated with the severity of illness, body mass index, and resting energy expenditure, but not with substrate oxidation rates. In addition, the severity of IR did not vary among patients with different admission diagnoses.

Insulin sensitivity is characterized by insulin-stimulated glucose metabolism in skeletal muscle. We hypothesized that carbohydrate metabolism and storage might be under transcriptional control. To test this hypothesis, we fed insulin-sensitive males (glucose disposal rate, 14.7 +/- 4.1 mg/kg fat-free mass [FFM] per minute) an isoenergetic high-fat/low-carbohydrate diet (HF/LCD) for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarrays revealed a total of 369 genes of 18861 genes on the arrays were differentially regulated in response to diet (Bonferonni adjusted P < .01). A similar experiment was conducted in mice with a 3-week intervention using a control group and an HF/LCD group to offset the lack of a control group within the human cohort. As part of an analysis of results previously published from this data set, 7 genes in the carbohydrate metabolism pathway changed in response to the HF/LCD, and 3 genes were confirmed by quantitative reverse transcriptase-polymerase chain reaction: fructose-2,6-biphosphatase 3 (PFKFB3), pyruvate dehydrogenase kinase, isoenzyme 4 (PDK4), and glycogen synthase 1 (muscle). In a separate experiment, we fed C57Bl/6J mice an HF/LCD for 3 weeks and found that the same glucose metabolism genes were changed by approximately 70% on average. Fructose-2,6-biphosphatase 3 and pyruvate dehydrogenase kinase, isoenzyme 4 increased and glycogen synthase 1 (muscle) decreased. Combined, these results suggest a mechanism whereby HF/LCD regulates the genes necessary for glucose utilization and storage vis-á-vis transcriptional control.

This study investigated the combined effects of endurance training and aging on substrate oxidation during exercise. Thirty-one healthy male subjects in 4 groups (8 middle-aged trained cyclists, 8 young trained cyclists, 7 middle-aged sedentary men, and 8 young sedentary men) performed 2 50-minute cycle ergometer exercise tests, below and above (+/-15%) their individual ventilatory threshold (VT). Substrate oxidation was evaluated by indirect calorimetry during the steady-state tests. Aging decreased carbohydrate (CHO) use (P<.05) in all subjects regardless of fitness status or exercise intensity. However, it declined 2-fold less in the trained men (P<.05) and was associated with a stronger epinephrine response (P<.05). During hard-intensity exercise, endurance training increased by 100% CHO use in the older men (P<.05). In the younger men, training increased fat oxidation but did not change CHO oxidation, resulting in a marked decrease in the ratio between CHO and fat used at high-intensity exercise (-93%; P<.05). These data suggest an age-related decline in the use of CHO as an energy source in exercising men, independent of intensity level. This decline, however, is attenuated in well-trained men for exercise intensities above the VT. In view of these findings, we hypothesize that cycling training performed at a specific exercise intensity (ie, 15% above VT) may improve CHO mobilization and use in middle-aged men.

The purpose of the present study was to investigate the thermic effect of food (TEF) and sympathetic nervous system (SNS) activity in obese boys. Ten obese (9.2+/-0.4 years) and 13 lean boys (8.8+/-0.4 years) were examined for energy expenditure and fat oxidation measured via indirect calorimetry for 3 hours after a high-carbohydrate (HC; 70% carbohydrate, 20% fat, and 10% protein) or a high-fat (HF; 20% carbohydrate, 70% fat, and 10% protein) meal served on 2 different days at random. The activity of the SNS was assessed by means of a power spectral analysis of the heart rate variability. The TEF, expressed as a percentage of the consumed energy, was significantly lower in obese boys than in lean boys after the HC meal; however, such a difference was not observed after the HF meal. Multiple regression analysis revealed that obesity was a significant variable contributing to the variances in the TEF induced by the HC meal. Moreover, after the HC meal, the boys with a recent onset of obesity (duration, <3 years) manifested a lower TEF as well as a reduced very low frequency component of the heart rate variability, an index of thermoregulatory SNS functions, compared with the remaining obese and lean boys. In conclusion, obese boys possessed normal metabolic and sympathetic responses to the HF meal but showed a diminished thermogenic response to the HC meal, especially during the early phase of obesity.

An intrauterine environment may play a role in predisposing a developing fetus to metabolic diseases during adulthood. We investigated the hypothesis that a maternal diet high in omega-6 polyunsaturated fat can modify the programming of an offspring's glucose tolerance, insulin sensitivity, body composition, lipid metabolism, and insulin signaling. High omega-6 polyunsaturated fat diets were fed to female rats 4 weeks before mating and throughout the gestation period. The offspring were maintained on chow diet. At 3 months of age, indirect calorimetry, oral glucose tolerance tests, and dual x-ray absorptiometry measurements were performed. Triglyceride content and beta-hydroxyacyl coenzyme A dehydrogenase activity were determined in the liver and quadriceps muscle. Expression levels of key insulin signaling pathway proteins were measured in the liver and quadriceps muscle of the 3-month-old offspring. Offspring from the fat-fed dams had significantly increased proportions of both total body fat and abdominal fat. All offspring displayed normal insulin sensitivity and glucose tolerance, although the offspring from the fat-fed dams were significantly more hyperinsulinemic 15 minutes after an oral glucose challenge. Whole body fuel oxidation was not altered. The offspring of fat-fed dams had significantly elevated liver triglyceride content. Insulin signaling protein expression levels in the offspring of fat-fed dams were consistent with reduced hepatic insulin sensitivity but increased quadriceps insulin sensitivity. A maternal diet high in omega-6 polyunsaturated fat evokes programming within the metabolic processes of the offspring that may predispose the offspring to the development of metabolic diseases.

Obese, insulin-resistant patients have been shown to have metabolic inflexibility. The goal of this study was to examine the effect of insulin administration on energy metabolism in lean, type 1 diabetic (DM1) patients. Eleven DM1 patients without vascular complications and 11 healthy controls (C) were examined. We performed a 2-step hyperinsulinemic euglycemic clamp (240 minutes; period 1: 1 mU. kg(-1). min(-1) and period 2: 10 mU. kg(-1). min(-1)) combined with indirect calorimetry during basal period B (B, -45 to 0 minutes), period 1, and period 2 of the clamp. The metabolic clearance rates of glucose (MCR) were lower in DM1 compared with C in period 1 (12.54 +/- 3.38 v 17.41 +/- 6.18 mL. kg(-1). min(-1); P <.02), as well as in period 2 (21.63 +/- 6.47 v 26.61 +/- 4.45 mL. kg(-1). min(-1); P <.05). Basal respiratory quotient (RQ) was lower in DM1 compared with C (0.72 +/- 0.04 v 0.75 +/- 0.04; P <.03). Insulin administration was accompanied by an increase in RQ in both groups, which was lower in DM1 compared with C (period 1: +0.09 +/- 0.04 v +0.11 +/- 0.07; P <.001; period 2: +0.13 +/- 0.04 v +0.16 +/- 0.04; P <.001). Glucose oxidation did not differ between the groups in period B; however, it was lower in DM1 compared with C in periods 1 (1.17 +/- 0.67 v 3.28 +/- 1.11 mg. kg(-1). min(-1); P <.003); and 2 (2.10 +/- 0.64 v 3.28 +/- 0.93 mg. kg(-1). min(-1); P <.009). Lipid oxidation was higher in DM1 in all periods compared with C; period B (3.28 +/- 0.77 v 1.16 +/- 0.55 mg. kg(-1). min(-1); P <.001), period 1 (1.10 +/- 0.41 v 0.67 +/- 0.54 mg. kg(-1). min(-1); P <.05), and period 2 (0.99 +/- 0.29 v 0.52 +/- 0.58 mg. kg(-1). min(-1); P <.01). The groups did not differ in protein oxidation. In conclusion, DM1 patients with secondary insulin resistance (IR) are characterized by metabolic inflexibility manifesting itself by smaller increases in RQ and glucose oxidation after insulin administration during the euglycemic clamp.

The mechanism underlying hypertriglyceridemia-associated insulin resistance in humans remains poorly understood. It has been proposed that hypertriglyceridemia only produces insulin resistance when associated with an increased lipid delivery to muscle. Accordingly, hypertriglyceridemia secondary to a decreased clearance of triglyceride-rich particles should not cause insulin resistance. To verify this hypothesis, we assessed whole body and adipose tissue insulin sensitivity in 15 healthy male volunteers before and after a 5-day administration of isotretinoin (1 mg/kg/d), a vitamin A derivative that decreases the clearance of triglyceride-rich particles. Whole body insulin-mediated glucose disposal (6,6 (2)H(2)glucose), glucose oxidation (indirect calorimetry), lipolysis ((2)H(5) glycerol), and subcutaneous adipose lipolysis (microdialysis) were evaluated during a 3-step hyperinsulinemic euglycemic clamp. Isotretinoin increased plasma triglyceride from 0.97 +/- 0.15 to 1.30 +/- 0.22 mmol/L (P <.02), but did not change whole body insulin-mediated glucose disposal and lipolysis. These observations are consistent with an isotretinoin-induced inhibition of very-low-density lipoprotein (VLDL)-triglyceride clearance. The suppression of endogenous glucose production and the reduction in subcutaneous adipose glycerol concentrations by insulin remained equally unaffected after isotretinoin administration. We conclude that the impaired clearance of triglyceride-rich particles secondary to a 5-day isotretinoin administration does not impair insulin-mediated antilipolysis or glucose disposal. The data support the concept that hypertriglyceridemia-associated insulin resistance develops primarily when triglyceride production is increased.

The pathophysiology of insulin resistance in human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is not fully clarified. We investigated 18 men with HALS and 18 HIV-positive males without lipodystrophy (control subjects). Duration and modality of antiretroviral therapy were similar between study groups. A hyperinsulinemic euglycemic clamp showed an impaired glucose disposal rate (GDR) in HALS patients (5.6 v 8.3 mg glucose/min. kg(FFM), P =.0006). As demonstrated by indirect calorimetry, HALS patients showed an impaired nonoxidative glucose metabolism (NOGM, 2.2 v 4.2, P =.006), whereas levels of basal and insulin-stimulated oxidative glucose metabolism (OGM) (2.4 v 2.3, P =.55, and 3.3 v 4.0, P =.064, respectively) were not significantly different between groups. Despite comparable total fat masses, dual energy x-ray absorptiometry (DEXA) scans showed that the percentage of limb fat (ie, peripheral-fat-mass/[peripheral-fat-mass + trunk-fat-mass]. 100%) was reduced in HALS patients (36% v 46%, P =.0002). Multiple linear regression analysis indicated that percentage of limb fat explained 53% of the variability of GDR and 45% of the variability of NOGM in HALS patients. In HALS patients, leg fat mass correlated positively with NOGM (r =.51, P <.05), whereas abdominal fat mass and NOGM did not correlate (P =.91). Analyzing the relationship between first phase insulin secretion and insulin sensitivity, 6 HALS patients compared with none of the control subjects exhibited impaired insulin secretion (P <.05). Our data suggest that fat redistribution independently of antiretroviral therapy is highly related to insulin resistance in HALS patients. Furthermore, in HALS patients, impaired glucose metabolism most likely relates to decreased NOGM and to defects in beta-cell function.

Insulin resistance is associated with increased circulating lipids and skeletal muscle lipid content. Chronic nicotinic acid (NA) treatment reduces insulin sensitivity and provides a model of insulin resistance. We hypothesized that the reduction in insulin sensitivity occurs via elevation of circulating nonesterified fatty acids (NEFAs) and an increase in intramyocellular lipid (IMCL). A total of 15 nondiabetic males (mean age 27.4 +/- 1.6 years) were treated with NA (500 mg daily for 1 week, 1 g daily for 1 week). Insulin sensitivity (glucose infusion rate [GIR]) was determined pre- and post-NA by euglycemic-hyperinsulinemic clamp. Substrate oxidation was determined by indirect calorimetry. Skeletal muscle lipid was assessed by estimation of long-chain acyl-CoA (LCACoA) and triglyceride (TG) content and by (1)H-magnetic resonance spectroscopy quantification of IMCL (n = 11). NA reduced GIR (P =.03) and nonoxidative glucose disposal (P <.01) and increased fasting NEFAs (P =.01). The decrease in GIR related significantly to the increase in fasting NEFAs (r(2) =.30, P =.03). The intrasubject increase in basal and clamp fat oxidation correlated with the decrease in GIR (r(2) =.45, P <.01 and r(2) =.63, P <.01). There were no significant changes in muscle LCACoA, TG, or IMCL content. Therefore, induction of insulin resistance by NA occurs with increased availability of circulating fatty acids to muscle rather than with increased muscle lipid content.

To determine whether total energy expenditure (TEE) is increased in the human immunodeficiency virus (HIV) lipodystrophy syndrome, we compared energy expenditure (EE) and substrate oxidation rates in 12 HIV-infected men with lipodystrophy, 7 HIV-infected men without lipodystrophy, and 14 healthy controls. TEE and nutrient oxidation rates were assessed by whole-room indirect calorimetry. Resting energy expenditure (REE) was measured by indirect calorimetry using the open-circuit technique. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA). Insulin sensitivity was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. TEE adjusted for lean body mass (LBM) was significantly higher in the HIV-infected group with lipodystrophy compared to HIV-infected patients without lipodystrophy (2,873.3 +/- 69 v 2,573.9 +/- 92 kcal/d, P =.02) and compared to healthy controls (2,873.3 +/- 69 v 2,404.0 +/- 64 kcal/d, P <.001). REE and sleeping metabolic rate (SMR) adjusted for LBM were also significantly higher in the HIV-infected group with lipodystrophy compared to both HIV-infected and healthy controls. Carbohydrate oxidation rates adjusted for LBM were higher in men with HIV lipodystrophy as compared to healthy controls (362.5 +/- 23 v 250.0 +/- 22 g/d, P = <.01) and tended to be higher as compared to HIV-infected controls (362.5 +/- 23.6 v 297.3 +/- 31 g/d, P =.1). In conclusion, TEE and carbohydrate oxidation are increased in the HIV lipodystrophy syndrome. The increase in TEE appears to be due to increases in REE. The pathogenesis of elevated EE in HIV lipodystrophy and other forms of lipodystrophy remains to be determined., (Copyright 2003 Elsevier Inc. All rights reserved.)

The respective effects of the level of glycogen stores and the size of the glucose load on the pathways of carbohydrate (CHO) metabolism were compared over the 5-hour period following glucose ingestion in normal human subjects. For this purpose, labeling of the oral glucose load with [3-(3)H]- and [U(14)C] glucose was combined with indirect calorimetry. In group I, 75 g glucose was given to subjects who had either been "fed" with intravenous (IV) glucose or fasted for 13, 24, or 36 hours, or 4 days. In fed versus 4-day-fasted subjects, net CHO storage averaged approximately 15 versus 63 g/5 h (P <.001). About 83% of the increase in fasted subjects was due to suppression of glycogen breakdown, with only minimal stimulation of glycogen synthesis from oral glucose. Over the whole range of nutritional conditions tested, a strong positive correlation existed between basal CHO oxidation and glycogen breakdown occurring during the oral glucose tolerance test (OGTT), suggesting that the initial degree of repletion of hepatic glycogen stores is a major determinant of postprandial glycogen turnover. In group II, OGTTs with 33 and 100 g glucose were compared in 13-hour-fasted subjects. Net storage rose from approximately -6 to approximately 37 g/5 h (P <.001) solely because of an increase in glycogen synthesis with no inhibition of glycogen turnover. Overall, these results show that the initial dietary state and the size of the glucose load modulate postprandial net CHO accumulation by different mechanisms., (Copyright 2003, Elsevier Science (USA). All rights reserved.)

Fatty acids fulfill important roles in physiology. The plasma concentrations of fatty acids are principally regulated by insulin, which suppresses the release of fatty acids from lipid stores, and catecholamines, which increase their release from lipid stores. Although insulin regulates the concentration of plasma free fatty acids (FFAs), little is known about the relative effects of insulin on the saturated compared with the unsaturated plasma fatty acids. In the current study, we specifically measured the plasma concentration of 3 saturated and 4 unsaturated fatty acids along with an estimate of lipolytic activity using a stable isotope of glycerol during a 3-hour, 1-step, euglycemic clamp study in humans. The data showed the expected decline in plasma fatty acids from 0.26 +/- 0.02 to 0.06 +/- 0.01 micromol/mL. Saturated fatty acids were reduced from 0.12 +/- 0.01 to 0.05 +/- 0.005 micromol/mL and unsaturated fatty acids were reduced from 0.11 +/- 0.01 to 0.01 +/- 0.001 micromol/mL after 3 hours of insulin infusion. At baseline, the ratio of saturated to unsaturated fatty acid was 55:45, which increased to 82:18 by the end of study. The changes in fatty acids were evident within 1 hour. Whole body lipolytic rates were measured with deuterated glycerol and decreased from 1.48 +/- 0.56 micromol x kg(-1) x min(-1) to 0.75 +/- 0.34 micromol x kg(-1) x min(-1). Baseline postabsorptive plasma fatty acid concentrations were significantly correlated to insulin sensitivity (M value) as measured during the euglycemic clamp. There were no significant differences between the more insulin-sensitive subjects when compared with the more insulin-resistant subjects with respect to the relative decreases in saturated and unsaturated fatty acids during insulin infusion. These data demonstrate a sustained differential effect of insulin on the plasma fatty acid profile., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

It remains unclear how ethanol truly impacts body weight and energy balance. Dietary intake studies suggest that energy intake is greater in ethanol consumers; however, large population studies have shown that ethanol intake is in fact not associated with increased body weight. Energy expenditure (EE) has been shown to be either mildly increased or unchanged after acute ethanol intake, but the effects of chronic ethanol intake on energy balance have not been well studied. The following study was performed to prospectively examine the effects of chronic moderate ethanol consumption and its interactions with the macronutrient composition of the diet on energy balance. Male Sprague-Dawley rats (n = 16) were first randomized to either a low-fat diet (LF = 10% fat, 70% carbohydrate, 20% protein) or a high-fat diet (HF = 30% fat, 50% carbohydrate, 20% protein). Rats were then randomized to receive either a 5% ethanol solution (ethanol) or water (control) as their drinking supply (day 14) for a total of 4 groups (LF-ethanol, LF-control, HF-ethanol, HF-control; n = 4 per group). On days 7, 21, and 42, indirect calorimetry was performed. Body weight and energy intake were measured throughout the study period. The rate of weight gain was unaffected by ethanol but was increased on the HF diet. Ethanol intake averaged 14.56% +/- 1.16% of total caloric intake. Both ethanol groups compensated for added ethanol calories by reducing their intake of diet, so that total energy intake was similar in all groups. As expected, respiratory quotient decreased in both ethanol groups (LF: 0.92 to 0.88; HF: 0.88 to 0.86; P <.05). However, EE was not affected by ethanol intake. These findings demonstrate that male Sprague-Dawley rats fully compensate for the calories associated with moderate chronic ethanol consumption and maintain energy balance regardless of the fat content of the baseline diet. This compensation suggests that ethanol calories are sensed, producing an appropriate reduction in the intake of other nutrients, and/or that ethanol impacts the regulation of dietary intake mediators., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

The purpose of the present work was to have a closer view on the changes in the regulation of glycogen synthase (GS) activity by insulin in relationship with the impairment of nonoxidative glucose disposal in human obesity. Obese patients with normal glucose tolerance (12), impaired glucose tolerance (11), diabetes (10), and lean control subjects (15) participated to the study. A euglycemic, hyperinsulinemic clamp was performed and associated with indirect calorimetry. Muscle needle biopsies were taken before and at the end of the 2-hour clamp for measurements of glycogen synthase fractional velocity and total activity. Total GS activity was significantly decreased (P <.05), while its percent activation by insulin was still normal in the obese glucose-tolerant group, and nonoxidative glucose disposal was decreased by 56% (P <.001) and glucose oxidation still normal. Total GS activity was decreased by about 50% (P <.01) and GS was unresponsive to insulin in the glucose-intolerant and diabetic groups. In conclusion, our data show that insulin-stimulated nonoxidative glucose disposal and total glycogen synthase are very early defects observed in obese patients., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

The purpose of this study was to evaluate the effect of successful laser-assisted uvulopalatoplasty (LAUP) on sleep energy expenditure (EE) in obstructive sleep apnea syndrome (OSAS) patients. Fifteen healthy subjects (group I) and 25 patients with moderately severe or severe OSAS (group II) proven by overnight sleep study and who wanted LAUP were enrolled. During the night of the sleep studies, EE was measured with a metabolic cart (indirect calorimetry with canopy), including basal metabolic rate (BMR), mean sleep EE, lowest sleep EE, ratios of mean sleep EE/BMR, and lowest sleep EE/BMR. For the OSAS patients, a second sleep study with EE measurement was performed 3 months after LAUP. Based on this assessment of their sleep architecture, they were divided into 2 groups: responders (group IIa) and nonresponders (group IIb). The mean sleep EE, the ratio of mean sleep EE/BMR and lowest EE/BMR were significantly higher in group II than group I. After LAUP in group II, 6 patients were found to be responders (group IIa) and 19 patients were nonresponders (group IIb). Group IIa had decreased mean sleep EE, ratios of mean sleep EE/BMR, and lowest sleeping EE/BMR after LAUP than before LAUP compared with no significant changes in group IIb after LAUP. In conclusion, there is increased sleep EE in moderately severe OSAS patients when compared with normal controls. LAUP, when effective in reversing the sleep abnormalities, also normalizes the sleep EE. If it does not adequately treat the OSAS, however, the sleep EE remains abnormal., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Changes in glucose and fat metabolism associated with human immunodeficiency virus (HIV) infection have received attention because of the development of glucose intolerance, dyslipidemia, and lipodystrophy associated with protease inhibitor (PI) therapy. The response to ingested [13C]glucose (1.4 g/kg) was determined in 9 asymptomatic male HIV patients before and after 4.8 months of PI therapy (nelfinavir, 2,250 mg/d) compared with 9 matched seronegative HIV controls. No significant difference was observed for basal plasma glucose, insulin, and C-peptide concentrations between controls and patients before PI therapy. After 4.8 months of PI therapy, basal plasma glucose concentration was slightly, but significantly, increased (approximately 15%) compared with controls or HIV patients prior to receiving PI therapy. Over the first hour following ingestion of the glucose load, plasma glucose and insulin concentrations were higher in HIV patients than in controls, both before (approximately 15% and approximately 29%, respectively) and after (approximately 32% and approximately 43%, respectively) PI therapy. In addition, plasma C-peptide concentration was approximately 61% higher after PI therapy. The oxidation rate of fat, endogenous, and exogenous glucose was computed from the VO2 and respiratory exchange ratio corrected for protein oxidation and from 13C/12C in expired CO2. The only difference between controls and patients both before and after PI therapy was observed over the first 120 minutes following ingestion of the glucose load, when HIV patients oxidized approximately 18% more glucose and approximately 19% less fat than controls. This was not due to a larger oxidation rate of exogenous glucose, but to a larger oxidation rate of endogenous glucose (approximately 50%) in patients compared with controls. These data indicate that HIV infection is associated with minor changes in glucose metabolism, and that PI therapy with nelfinavir for 4.8 months only slightly further impairs glucose metabolism as assessed in response to a large oral glucose load. However, the larger stimulation of total and endogenous glucose oxidation and the larger reduction in fat oxidation, observed in the metabolic response to the glucose load in HIV patients, over time, could result in the accumulation of body fat and could contribute to lipodystrophy., (Copyright 2002 by W.B. Saunders Company)

This study determined the effects of 28 days of oral creatine ingestion (days 1 to 5 = 20g/d; [5 g 4 times daily]: days 6 to 28 = 10 g/d; [5 g twice daily]) alone and with resistance training (5 hours/week) on resting metabolic rate (RMR), body composition, muscular strength (1RM), and limb blood flow (LBF). Using a double-blind, placebo-controlled design, 30 healthy male volunteers (21 +/- 3 years; 18 to 30 years) were randomly assigned to 1 of 3 groups; pure creatine monohydrate alone (Cr; n = 10), creatine plus resistance training (Cr-RT; n = 10), or placebo plus resistance training (P-RT; n = 10). Body composition (DEXA, Lunar DPX-IQ), body mass, bench, and leg press 1RM (isotonic), RMR (indirect calorimetry; ventilated hood), and forearm and calf LBF (venous occlusive plethysmography) were obtained on all 30 subjects on 3 occasions beginning at approximately 6:00 AM following an overnight fast and 24 hours removed from the last training session; baseline (day 0), and 7 days and 29 days following the interventions. No differences existed among groups at baseline for any of the variables measured. Following the 28-day interventions, body mass (Cr, 73.9 +/- 11.5 v 75.6 +/- 12.5 kg; Cr-RT, 78.8 +/- 6.7 v 80.8 +/- 6.8 kg; P <.01) and total body water (Cr, 40.4 +/- 6.8 v 42.6 +/- 7.2 L, 5.5%; Cr-RT, 40.6 +/- 2.4 v 42.3 +/- 2.2 L, 4.3%; P <.01) increased significantly in Cr and Cr-RT, but remained unchanged in P-RT, whereas, fat-free mass (FFM) increased significantly in Cr-RT (63 +/- 2.8 v 64.7 +/- 3.6 kg; P <.01) and showed a tendency to increase in Cr (58.1 +/- 8.1 v 59 +/- 8.8 kg; P =.07). Following the 28-day period, all groups significantly increased (P <.01) bench (Cr, 77.3 +/- 4 v 83.2 +/- 3.6 kg; Cr-RT, 76.8 +/- 4.5 v 90.5 +/- 4.5 kg; P-RT, 76.0 +/- 3.4 v 85.5 +/- 3.2 kg), and leg press (Cr, 205.5 +/- 14.5 v 238.6 +/- 13.2 kg; Cr-RT, 167.7 +/- 13.2 v 238.6 +/- 17.3 kg; P-RT, 200.5 +/- 9.5 v 255 +/- 13.2 kg) 1RM muscular strength. However, Cr-RT improved significantly more (P <.05) on the leg press 1RM than Cr and P-RT and the bench press 1RM than Cr (P <.01). Calf (30%) and forearm (38%) LBF increased significantly (P <.05) in the Cr-RT, but remained unchanged in the Cr and P-RT groups following the supplementation period. RMR expressed on an absolute basis was increased in the Cr (1,860.1 +/- 164.9 v 1,907 +/- 173.4 kcal/d, 2.5%; P <.05) and Cr-RT (1,971.4 +/- 171.8 v 2,085.7 +/- 183.6 kcal/d, 5%; P <.05), but remained unchanged from baseline in P-RT. Total cholesterol decreased significantly in Cr-RT (-9.9%; 172 +/- 27 v 155 +/- 26 mg/dL; P <.01) compared with Cr (174 +/- 46 v 178 +/- 43 mg/dL) and P-RT (162 +/- 32 v 161 +/- 36 mg/dL) following the 28-day intervention. These findings suggest that the addition of creatine supplementation to resistance training significantly increases total and fat-free body mass, muscular strength, peripheral blood flow, and resting energy expenditure and improves blood cholesterol., (Copyright 2001 by W.B. Saunders Company)

The alanine to threonine substitution at codon 54 (Ala54Thr) of the fatty acid binding protein 2 (FABP2) gene has been reported to be associated with increased fat oxidation and insulin resistance in several populations. It has been hypothesized that Ala54Thr substitution results in enhanced intestinal uptake of fatty acids and thereby an impairment of insulin action, but this hypothesis has not been proven in vivo. We studied the association between the Ala54Thr polymorphism of the FABP2 gene and intestinal (3)H-oleic acid absorption, as well as basal insulin level, basal metabolic rate, and fat oxidation rate in 96 healthy young Korean men. Among our subjects, the allele frequency of the Ala54Thr substitution was 0.34. Subjects with Thr54-encoding allele were found to have a higher mean fasting plasma insulin concentration and a higher basal fat oxidation rate compared with the subjects who were homozygous for the Ala54-encoding allele. However, there was no significant difference in basal metabolic rate or (3)H-oleic acid absorption according to the FABP2 gene polymorphism. These results suggest that the Ala54Thr substitution in the FABP2 gene is associated with increased fat oxidation and hyperinsulinemia in normal Korean men, but these effects are not mediated by an increase in the intestinal fatty acid absorption., (Copyright 2001 by W.B. Saunders Company)

D-Fructose has been found to increase uric acid production by accelerating the degradation of purine nucleotides, probably due to hepatocellular depletion of inorganic phosphate (Pi) by an accumulation of ketohexose-1-phosphate. The hyperuricemic effect of D-tagatose, a stereoisomer of D-fructose, may be greater than that of D-fructose, as the subsequent degradation of D-tagatose-1-phosphate is slower than the degradation of D-fructose-1-phosphate. We tested the effect of 30 g oral D-tagatose versus D-fructose on plasma uric acid and other metabolic parameters in 8 male subjects by a double-blind crossover design. Both the peak concentration and 4-hour area under the curve (AUC) of serum uric acid were significantly higher after D-tagatose compared with either 30 g D-fructose or plain water. The decline in serum Pi concentration was greater at 50 minutes after D-tagatose versus D-fructose. The thermogenic and lactacidemic responses to D-tagatose were blunted compared with D-fructose. D-Tagatose attenuated the glycemic and insulinemic responses to a meal that was consumed 255 minutes after its administration. Moreover, both fructose and D-tagatose increased plasma concentrations of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). The metabolic effects of D-tagatose occurred despite its putative poor absorption.

Fructose-1,6-diphosphate (FDP) is an important naturally occurring intracellular metabolite with a direct regulatory role in many metabolic pathways. The most important and widely studied of the FDP effects has been its regulation of glycolysis, particularly the enzyme that synthesizes FDP--phosphofructokinase (PFK). Since it was observed experimentally that FDP does indeed modulate carbohydrate metabolism, we investigated whether FDP would similarly enhance carbohydrate utilization in man. The study used indirect calorimetry and was open to healthy adults (N = 45) of either sex and above legal age. After a steady metabolic state was obtained, 5 g of FDP (10%) was infused into a brachial vein. In 10 subjects, glucose (5 g) or FDP (5 g) was sequentially infused. The rapid intravenous infusion of FDP produced a slight but significant decrease in heart and respiration rates (P < .05). A significant increase in the serum concentration of inorganic phosphate (P < .0001) and the intraerythrocytic concentration of adenosine triphosphate (ATP) (P < .01) was also observed. The FDP infusion produced a decrease in plasma cholesterol and triglycerides (P < .001 and P < .01, respectively). The indirect calorimetric data indicate that the infusion produced a highly significant increase in the respiratory quotient ([RQ] P < .0001) and the energy derived from carbohydrates (P < .0001) and a significant decrease in the energy derived from lipids (P < .0001). Glucose infusion did not cause changes in any of the parameters. These data indicate that carbohydrate metabolism is stimulated by FDP.