Why do some individuals gain weight in response to overeating, whereas others do not? A study in this week9s issue by Levine et al., discussed in the Perspective by Ravussin and Danforth, suggests that differences in fat gain can be accounted for by the energy expended in nonvoluntary physical activities such as fidgeting and maintenance of posture, termed nonexercise activity thermogenesis (NEAT). The underlying mechanism that allows humans to activate NEAT in response to overeating will require further study.

Stimulation of beta3-adrenoceptors by selective agonists improves insulin action and stimulates energy metabolism in various rodent models of obesity and type 2 diabetes. Whether selective beta3-adrenoceptor stimulation exerts metabolic actions in humans remains to be proven. The effects of a highly selective beta3-adrenoceptor agonist on insulin action, energy metabolism, and body composition were assessed in 14 healthy young lean male volunteers (age 22.5 +/- 3.3 years, 15 +/- 5% body fat [mean +/- SD]) randomly assigned to 8 weeks of treatment with either 1,500 mg/day of CL 316,243 (n = 10) or placebo (n = 4). Insulin-mediated glucose disposal (IMGD), nonoxidative glucose disposal (NOGD), oxidative glucose disposal (OGD) (indirect calorimetry), and splanchnic glucose output (SGO; beta3-[H3]glucose) were determined during a 100-min hyperinsulinemic-euglycemic glucose clamp (40 mU x m(-2) x min(-1)) before and after 4 and 8 weeks of treatment. The 24-h energy expenditure (24-EE), 24-h respiratory quotient (24-RQ), and the oxidation rates of fat and carbohydrate were determined in a respiratory chamber before and after 8 weeks. After 4 weeks, treatment with CL 316,243 increased IMGD (+45%, P < 0.01) in a plasma concentration-dependent manner (r = 0.76, P < 0.02). This effect was due to an 82% increase in NOGD (P < 0.01), while OGD and SGO remained unchanged. The effects on insulin action were markedly diminished after 8 weeks; this was significantly related to an unexpected decline in the plasma concentrations of CL 316,243 (-36%, P = 0.08). At this time, 24-RQ was lowered (P < 0.001), corresponding to a 23% increase in fat oxidation (P < 0.01) and a 17% decrease in carbohydrate oxidation (P = 0.05). The 24-EE after 8 weeks did not differ from baseline, and there was no change in body weight or body composition. Plasma concentrations of glucose, insulin, and leptin were unaffected by treatment, while free fatty acid concentrations increased by 41% (P < 0.05), again linearly with the achieved plasma concentration of CL 316,243 (r = 0.67, P < 0.05). Treatment with CL 316,243 had no effect on heart rate or blood pressure and caused no cases of tremors. We conclude that treatment of lean male subjects with CL 316,243 increases insulin action and fat oxidation, both in a plasma concentration-dependent manner. This is the first study to demonstrate unequivocal metabolic effects of a highly selective beta3-adrenoceptor agonist in humans.

The effects of exercise training and of its interaction with the genotype on components of energy expenditure and related hormones were examined in young male monozygotic twins. Energy intake was maintained at the pretraining level for a 93-day training period. The estimated net energy deficit induced by training was 244 MJ and was associated with a 5-kg body weight loss that was almost entirely explained by body fat loss. Resting metabolic rate (RMR) was significantly decreased by 8% after training despite the preservation of fat-free mass (FFM). Accordingly, plasma norepinephrine (NE) concentrations, NE appearance rate, and plasma levels of triiodothyronine (T3), free T3, and total thyroxine (T4) were lower after training. The energy cost of standardized exercise was also reduced after the training program. A modest to significant within-twin-pair resemblance was observed for absolute changes in the RMR, thermic effect of food, energy cost of exercise, NE clearance, and plasma concentrations of thyroid hormones. These results suggest that when exercise training is associated with a substantial negative energy balance, energy expenditure and levels of related hormones are decreased, and this effect is partly accounted for by heredity.

This study was designed to examine effects of alterations in energy balance on adaptive changes in components of total energy expenditure (TEE). Nineteen young healthy males were studied during a 10-day sedentary energy balance baseline period and then randomly assigned to one of four 10-day treatment groups: 1) no change in energy intake (EI) or physical activity (PA; energy balance at low energy flux), 2) EI increased by 50% with no change in PA (positive energy balance), 3) TEE increased by 50% by increasing PA, matched by a 50% increase in EI (energy balance at high energy flux), and 4) TEE increased by 50% by increasing PA with no change in EI (negative energy balance). TEE was measured with doubly labeled water, resting metabolic rate (RMR) by indirect calorimetry, and thermic response to feeding (TEF) by indirect calorimetry; energy expenditure of physical activity (EEPA) was estimated by subtracting RMR, TEF, and prescribed PA from TEE. TEE was significantly increased by PA (by design) but not EI. There was a significant main effect of intake and a significant intake-by-activity interaction for changes in RMR. In post hoc analysis, RMR was significantly increased during positive energy balance and energy balance at high energy flux relative to change in RMR when energy balance was maintained at low energy flux. A significant increase in RMR was also noted during negative energy balance after adjustment for change in fat-free mass. There was no significant difference in change in RMR among the three treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to compare the techniques of underwater weighing and analysis of total body water for estimating body fat with that derived from a 3-compartment model combining total body density and total body water. Body fat was estimated from: (1) body density using the Siri equation; (2) total body water assuming a hydration factor of 0.73 for fat free mass; and (3) the 3-compartment model combining body density and body water. The criterion method in this study was body fat mass determined from Siri's 3-compartment model. The subjects in this study included 10 obese men (41 +/- 10 years; 115.5 +/- 16.6 kg), 7 elderly men (68 +/- 6 years, 77.1 +/- 7.4 kg), and 18 young men (24 +/- 5 years; 71.0 +/- 9.2 kg). Body density was obtained by underwater weight with simultaneous determination of lung volume by helium dilution. Body water was obtained from zero-time extrapolation of isotope washout over 10-14 days following an oral dose of (H2O)-H-2 and (H2O)-O-18. Estimates of body fat derived from total body water were significantly higher than that derived from underwater weight in the elderly (1.4 +/- 1.5 kg; P < 0.05) and younger (3.0 +/- 2.8 kg; P < 0.001) men. In the obese subjects, there was no significant difference in body fat estimates between the two techniques (mean difference = 1.3 +/- 5.1 kg). The overestimation of body fat from total body water relative to underwater weight was negatively associated with body fat mass estimated from the 3-compartment model combining measurement of density and water (r = -0.35; P = 0.04). It is concluded that total body water overestimates body fat relative to underwater weight, and that this effect is more pronounced in leaner subjects.

The experimental reliability of measuring CO2 production rates (rCO2) with the doubly labeled water (DLW) technique was assessed in five young healthy men (23 (DLW) technique was assessed in five young healthy men (23 +/- 4 yr; 66.1 +/- 4.6 kg). To minimize the confounding effects of fluctuations in physical activity and eating patterns on variation in energy expenditure, the subjects lived under sedentary living conditions by confinement to their own room at a Clinical Research Center and were maintained on a fixed and known level of energy intake. rCO2 was determined in duplicate over two identical 9-day study periods after separate loading doses of deuterium and oxygen-18. Turnover rates were determined from multipoint sampling to reduce error from analytical uncertainty. Dilution spaces were determined by both the intercept and plateau methods. The average experimental variation for rCO2 estimates was approximately +/- 8.5% and was not significantly different among three published calculation models that differ in their assumptions regarding the relationship between the dilution spaces of deuterium and oxygen-18. The experimental reliability of +/- 8.5% exceeds theoretical values generated from calculations based on propagation of error from analytical uncertainty. Between subjects, the experimental variation ranged from 1 to 21%, and the half-width of the 95% confidence interval for the precision of rCO2 estimates was high (+/- 12 mol/day) relative to the mean reported value of approximately 16 mol/day.(ABSTRACT TRUNCATED AT 250 WORDS)

There is growing evidence of the involvement of sympathetic nervous system (SNS) activity in determining metabolic rate. Whole-body plasma norepinephrine turnover and its relationship to resting metabolic rate (RMR) and 24-hour energy expenditure (24EE) were compared in 14 Pima Indian men (25 +/- 4 years, 96 +/- 33 kg, 25% +/- 9% fat) and nine white men (25 +/- 3 years, 88 +/- 43 kg, 17% +/- 13% fat). Plasma norepinephrine turnover rate correlated strongly with body surface area (r = .76 and .54 for clearance and appearance, respectively) and fat-free mass (r = .74 and .52, respectively). However, independent of body size, there was no difference in either norepinephrine clearance or appearance rates between Pima Indian and white men. Norepinephrine appearance rate correlated positively with absolute values of 24EE and RMR, but not when adjusted for differences in body surface area or fat-free mass. However, norepinephrine appearance rate adjusted for differences in body size correlated with spontaneous physical activity. The results indicate that Pima Indian and white men have similar plasma norepinephrine appearance rates, but Pima Indians tend to be more resistant to beta-adrenergic stimulation. Although energy expenditure and SNS activity were not directly related, a higher SNS tone may either promote or reflect elevated levels of spontaneous physical activity and therefore influence both energy balance and body composition.

Short-term mixed calorie overfeeding increases basal energy expenditure in man but its effects on the thermic effect of a meal (TEM) are unclear. The thermogenic and hormonal responses to an 800-kcal liquid mixed meal were measured in six lean and six obese subjects during weight maintenance, during 18 d of overfeeding 1000 kcal/d, and during 18 d of a 589 kcal/d diet (obese subjects only). There was no change in the TEM in lean subjects between weight maintenance and overfeeding. In the obese group the TEM was lower during both overfeeding (p less than 0.05) and underfeeding (p less than 0.05) compared with weight maintenance. Overfeeding increased rates of net postprandial glucose oxidation and decreased lipid oxidation in the lean subjects only. Alterations in glucose oxidation rates and the insulin response to meals may contribute to an impaired TEM in human obesity during overnutrition.

Seven lean healthy young men were studied for 6 weeks during exposure to pharmacologic inhibition or stimulation of the sympathetic nervous system. For a period of 2 weeks their beta-adrenergic receptors were either blocked with propranolol hydrochloride (160 mg/d) or stimulated with terbutaline sulphate (15 mg/d). After a further 2 weeks of placebo administration (500 mg lactose/d), the subjects crossed over to the drug they had not been taking at the beginning of the experiment for another 14 days. During the last five days of each 2-week period, the subjects consumed a weight-maintaining diet, composed of 12% protein, 48% carbohydrate, and 40% fat. They consumed exactly the same menus on the same days during the subsequent study periods. Body weight and physical activity were measured every day for 6 weeks. Daily heart rate and nitrogen excretion were measured continuously for days at the end of each 2-week period, the last two days of which were spent in a respiration chamber where energy expenditure and a variety of metabolic parameters were measured. In the respiration chamber on the propranolol, placebo, and terbutaline treatments, respectively, significant differences were observed in mean daily heart rate (65 +/- 3, 75 +/- 4, and 84 +/- 4 beats/min), mean sleeping heart rate (51 +/- 2, 56 +/- 3, and 62 +/- 3 beats/min), nitrogen excretion (13.6 +/- 0.7, 12.6 +/- 0.6, and 11.9 +/- 0.6 g/d), fat oxidation (+1,045 +/- 95, +1,243 +/- 148, and +1,278 +/- 84 kcal/d) and thyroid hormones (12.0 +/- 0.7, 15.7 +/- 0.9, and 17.2 +/- 1.0 T3/T4 ratio).(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous respiratory-exchange measurements were performed on ten moderately obese and ten lean young women for 1 h before, 3 h during, and 3 h after either parenteral (IV) or intragastric (IG) administration of a nutrient mixture infused at twice the postabsorptive, resting energy expenditure (REE). REE rose significantly from 0.98 +/- 0.02 to 1.13 +/- 0.03 kcal/min (IV) and from 0.99 +/- 0.02 to 1.13 +/- 0.02 kcal/min (IG) in the lean group; from 1.10 +/- 0.02 to 1.27 +/- 0.03 kcal/min (IV) and from 1.11 +/- 0.02 to 1.29 +/- 0.03 (IG) in the obese group. These increases resulted in similar nutrient-induced thermogenesis of 10.0 +/- 0.7% (IV) and 9.3 +/- 0.9% (IG) in the lean group; of 9.2 +/- 0.7% (IV) and 10.1 +/- 0.8% (IG) in the obese. Nutrient utilization was comparable in both groups and in both routes of administration, although the response time to IG feeding was delayed. These results showed no significant difference in both the thermogenic response and nutrient utilization between moderately obese and control groups using acute IV or IG feeding.

Continuous respiratory exchange measurements were performed on 10 healthy young women for 1 h before, 3 h during, and 3 h after either parenteral (iv) or intragastric (ig) administration of a nutrient mixture (52% glucose, 18% amino acid, and 30% lipid energy) infused at twice the postabsorptive resting energy expenditure (REE). REE rose from 0.98 +/- 0.02 (iv) and 0.99 +/- 0.02 kcal/min (ig) postabsorptively to 1.13 +/- 0.03 (iv) and 1.13 +/- 0.02 kcal/min (ig), resulting in nutrient-induced thermogenesis of 10 +/- 0.6 and 9.3 +/- 0.9%, respectively, when related to the metabolizable energy. The respiratory quotient rose from preinfusion values of 0.81 +/- 0.02 (iv) and 0.80 +/- 0.01 (ig) to 0.86 +/- 0.01 (iv) and 0.85 +/- 0.01 (ig). After nutrient administration the respiratory quotient fell significantly to below the preinfusion values. Plasma glucose and insulin concentrations rose during nutrient administration but were higher during the intravenous route. It is concluded that, although the response time to intragastric administration was delayed, the thermic effects and overall substrate oxidations were comparable during intravenous or intragastric administration, albeit, at lower plasma glucose and insulin concentrations via the intragastric route.

To assess whether thermogenesis or sympathetic nervous system (SNS) function might differ between lean and obese human subjects, studies of thermic and sympathetic responses to standard stimuli were undertaken in Pima Indians, an ethnic group with a high prevalence of obesity. Plasma levels of norepinephrine (NE) and energy expenditure at rest and in response to feeding, exercise, and graded infusions of NE were compared in five lean and five obese Indians during a period of weight maintenance (WM), after 3 weeks of overfeeding (OF) and, in the obese, also after 6 weeks of underfeeding (UF). Basal energy expenditure, when adjusted for fat free mass, was equivalent during WM and increased 3% with OF (P < 0.01) in both groups. Thermic responses to exercise or a test meal did not differ in lean and obese and did not change with OF, while thermic responses to NE infusion fell during OF to a greater degree in obese than lean (P < 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P < 0.05). Although not quantitatively different in lean and obese, the plasma NE concentration appeared to vary more in response to feeding or dietary alteration in the obese than lean, a finding that may reflect lower plasma clearance of NE in the obese. These studies, therefore, raise the possibility that overfeeding in obese Pima Indians may limit the contribution of sympathetically mediated thermogenesis to energy expenditure, though the implications of this for body weight regulation are speculative.