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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. [ABSTRACT FROM AUTHOR]

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.

The hypothesis that exercise increases fat oxidation at rest independently of changes in energy balance, body composition, and/or lipolysis was tested in 21 volunteers. After a period of energy balance, volunteers were randomly allocated to one of four groups: control, overfed (OF), overfed and exercised (OF-EX), and exercised (EX). OF and OF-EX were overfed 50% excess of energy balance calories; OF-EX and EX spent 50% excess of energy balance calories during daily exercise sessions. Exercise increased fat oxidation at rest independently of dietary intake (OF-EX = + 22 +/- 2.4, EX = + 23 +/- 1.5 mg/min) and reduced carbohydrate oxidation (OF-EX = - 49 +/- 6.2, EX = - 46 +/- 5.4 mg/min). Volunteers in the OF group had an increase in carbohydrate oxidation (85 +/- 5.9 mg/min) and a decline in fat oxidation (- 33 +/- 1.4 mg/min). Protein oxidation did not change in any group. These changes occurred without a direct relation with changes in lipolysis and persisted even when expressed as a percentage or as an absolute equivalent of resting metabolic rate in calories. Thus exercise, independent of changes in energy intake and body composition and not related to changes in lipolysis, increases fat oxidation at rest, which may explain the beneficial effects of exercise in weight loss programs.

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 2H2O and H2(18)O. 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.

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 objective was to assess the effect of a new, highly selective beta 3-adrenergic agonist, CL-316,243 (CL) (J. D. Bloom, M. D. Dutia, B. D. Johnson, A. Wissner, M. G. Burns, E. E. Largis, J. A. Dolan, and T. H. Claus., J. Med. Chem. 35: 3081, 1992), on energy balance and brown and white adipose tissues (BAT and WAT, respectively) in young rats eating a high-fat diet to induce obesity. Chronic treatment with CL increased body temperature and 24-h energy expenditure, mainly by increasing resting metabolic rate. Food intake was not altered but carcass fat was reduced. Interscapular BAT was markedly hypertrophied, with three- to fourfold increases in the content of uncoupling protein (UCP) and cytochrome oxidase. Quantitative immunoelectron microscopy of interscapular BAT of CL-treated rats showed smaller mitochondria with an unchanged total amount of UCP per mitochondrion. The relative frequency of the four major cell types in BAT (mature brown adipocytes, preadipocytes, interstitial cells, endothelial cells) was not altered. The CL-induced hypertrophy differed from that induced by chronic stimulation by endogenous norepinephrine (as in cold-adaptation) in absence of hyperplasia (there was a slightly reduced DNA content), absence of an increase in the thyroxine (T4) 5'-deiodinase activity, and absence of a selective increase in UCP concentration. WAT depots weighed less and had fewer cells (lower DNA content) in the CL-treated rats. Some multilocular adipocytes appeared in these normally almost exclusively unilocular WAT depots (mesenteric, inguinal, epididymal, retroperitoneal). We conclude that CL not only promotes BAT mitochondrial proliferation and thermogenesis and overall energy expenditure and leanness, but also retards the development of WAT hyperplasia during the early stage of diet-induced obesity.

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)

Physiological sources of variation in the 2H-to-18O dilution space ratio (DSR) were examined in 34 males and 20 females (4-78 yr; 14.7-143.2 kg; 1.8-61.0% body fat). Dilution spaces were obtained by time 0 extrapolation of isotope washout over 10-14 days, and body composition was obtained by underwater weight (adults) or bioelectrical impedance (children). The mean DSR was 1.050 +/- 0.015 (range 1.029-1.111), significantly higher (P < 0.001) than the traditionally assumed value of 1.029 based on exchange over 4 h. Use of the value 1.029 causes a systematic 8% overestimate of energy expenditure from doubly labeled water, relative to use of the value 1.05. The DSR was not related to body composition or age but was significantly higher (P < 0.05) in males (1.052 +/- 0.016) than in females (1.044 +/- 0.012). This gender effect was not explained by differences in the number of exchangeable hydrogens in the body. We conclude 1) variation in the 2H-to-18O DSR is not explained by body composition but is influenced by the chemical availability of exchangeable hydrogens to undergo exchange; 2) because the DSR is not easily predicted, use of the observed dilution spaces are recommended; 3) if a fixed DSR is used, values of 1.044 and 1.052 are recommended in females and males, respectively.

We examined the effects of an 8-wk endurance training program (cycling exercise) on resting metabolic rate (RMR) and norepinephrine (NE) kinetics in 19 older persons (64 +/- 1.6 yr). Before and after training, RMR, NE kinetics, maximal O2 consumption (VO2max), body composition, supine blood pressure, estimated energy intake, and fasting levels of glucose, insulin, and thyroid hormones were measured. RMR increased 10% after training. Resting concentrations of NE increased 24% after training due to a 21% increase in NE appearance rate and no change in NE clearance. Training increased VO2max (14%; P less than 0.01) and energy intake (12%; P less than 0.01), whereas no change was noted in body composition. Supine blood pressure and plasma glucose were lower after training, whereas no change was noted in fasting levels of plasma insulin. The increase in RMR was associated with a higher rate of NE appearance (r = 0.57; P = 0.05) and with increase in energy intake (r = 0.56; P = 0.05). Together these two factors accounted for 49% (r2) of the variation of the change in RMR. Changes in blood pressure were not associated with changes in NE kinetics. We conclude that endurance training increases total energy expenditure in older individuals by the direct energy cost of physical activity and by elevating RMR. This increase is partially mediated by an increased NE appearance rate and increased food intake in healthy older individuals.

The associations among age, maximal aerobic capacity (VO2max), and body composition with resting metabolic rate (RMR), and fasting plasma hormones were examined in endurance-trained and untrained older and younger men. A higher RMR (approximately 6%; P less than 0.05), normalized per kilogram of fat-free weight (FFW), was found in endurance-trained younger and older men relative to untrained men. VO2max, independent of FFW, accounted for a significant portion of the variation in RMR. Fasting insulin and the fasting insulin-to-glucose ratio were higher in older men relative to younger men. This difference was diminished when differences in percent body fat were taken into account. Plasma thyroid hormones and glucagon were not associated with age, VO2max, or percent body fat. We conclude that endurance-trained and older men have a higher RMR than untrained younger and older men that is independent of differences in FFW. Plasma levels of thyroid hormones and glucagon are not influenced by age, VO2max, or adiposity in healthy nonobese men.

We examined the effects of age and physical activity on plasma norepinephrine (NE) kinetics in active and inactive older and younger men. NE kinetics were estimated by calculation of the rates of NE appearance and clearance during infusion of tritiated norepinephrine [( 3H]-NE). Older active men had the highest level of plasma NE (pg/ml) and NE appearance (microgram.min-1.FFW-1, where FFW is fat-free weight) relative to younger men and inactive older men. NE clearance (l.min-1.FFW-1) was not influenced by age or physical activity. No significant associations were noted between percent body fat, supine blood pressure with resting levels of NE, NE appearance, and NE clearance. We concluded that 1) chronic participation in physical activity by older men, but not younger men, is associated with higher resting levels of plasma NE and NE appearance and 2) the degree of adiposity does not influence plasma NE kinetics in healthy younger and older men. The level of physical activity is an influencing factor on plasma NE and NE appearance into circulation in healthy older men.

To determine whether acid-base balance regulates hydrogen ion production, seven obese volunteers were given NaHCO3 and NH4Cl (2 mmol.kg-1.day-1) during two separate 7-day fasts. On days 5-7 plasma bicarbonate was lower in the NH4Cl fasts (14.0 +/- 1.4 mM) than in the NaHCO3 fasts (18.3 +/- 1.1 mM), while urine pH and net acid excretion did not differ. Acid production (acid excretion minus intake) was greater by 204 mmol/day in the NaHCO3 fasts (274 +/- 16 mmol/day) than in the NH4Cl fasts (70 +/- 19 mmol/day). Ketoacid excretion, which reflected net ketoacid production, paralleled acid production, decreasing from 213 +/- 24 mmol/day in the NaHCO3 fasts to 67 +/- 18 mmol/day in the NH4Cl fasts. Thus, during starvation, alterations in hydrogen ion intake and the associated changes in acid-base balance modify the net production of endogenous acid by influencing the synthesis or utilization of ketoacids. Although the specific site of this metabolic regulation is undefined, these results indicate that systemic acid-base status can exert feedback control over hydrogen ion production.

To determine the effects of cafeteria feeding on brown (BAT) and white (WAT) adipose tissue cellularity, thermogenesis and body composition, male Sprague-Dawley rats were fed a cafeteria or a Purina chow diet for 52 days postweaning. Interscapular BAT (IBAT) was removed from subgroups of rats on each diet, and the animals continued on the same regimens. The IBAT weight of rats fed cafeteria diets was 160% of controls after 3 days and 220% after 52 days of the dietary regimens, and brown adipocyte numbers were 130 and 300% those of stock diet-fed rats, respectively, during the same period. Brown adipocyte diameters were initially greater in rats fed cafeteria diet than in rats fed stock diet but were similar after 52 days. Norepinephrine-stimulated thermogenesis was greater in rats fed cafeteria diets than in rats fed stock diet and was intermediate between the two in the IBAT-lipectomized group fed cafeteria diet. Surgical reduction of IBAT resulted in hypertrophy of WAT and an improved efficiency of weight gain, whereas body composition, WAT cellularity, and the efficiency of weight gain of similarly operated rats fed stock diet were unaltered from those of unoperated animals fed stock diet. These results are consistent with the development of a nutritionally induced hyperplasia and/or differentiation of BAT similar to that which follows cold acclimatization. BAT may play an active role in the expenditure of excess energy during periods of overnutrition, and thereby influence an animal's propensity for fatness.

The effects of hyper- and hypothyroidism on sympathetic nervous system activity and energy expenditure are well recognized. The impact of altered sympathetic nervous system activity on energy expenditure and thyroid hormone metabolism has not been well studied. We investigated the effects of orally administered terbutaline sulfate, a beta 2-receptor agonist (5 mg, three times per day for 2 weeks), on the activity of the sympathetic nervous system, energy expenditure, and thyroid hormone metabolism in six normal men, aged 21-36 yr. The cardiovascular, metabolic, and thermogenic responses to an infusion of the beta-adrenergic agonist isoproterenol were clearly blunted after 2 weeks of treatment with terbutaline sulfate, indicating down-regulation of beta-receptors and/or development of reduced sensitivity. There were no significant changes in the cardiovascular, metabolic, or thermogenic responses to an infusion of the alpha-adrenergic agonist phenylephrine. Basal metabolic rate was significantly increased by the chronic administration of terbutaline sulfate [5.040 +/- 0.167 (+/- SE) vs. 5.421 +/- 0.234 kJ/min; P less than 0.05]. There was a highly significant change in the serum T3 to T4 ratio (19.4 +/- 1.0 vs. 24.4 +/- 1.0; P less than 0.001). This was a result of increased serum T3 concentrations (136 +/- 9 vs. 160 +/- 14 ng/dl; P less than 0.05) and decreased serum T4 concentrations (7.2 +/- 0.8 vs. 6.7 +/- 0.8 micrograms/dl; P = NS). Chronic beta-receptor stimulation with terbutaline sulfate increases the basal metabolic rate and T3 concentrations. These changes occurred despite down-regulation of beta-receptors and/or decreased sensitivity in response to chronic terbutaline administration.

We have investigated the effect of FFA on the RIA of rT3 because of our previous findings of a correlation between serum rT3 values and increased FFA concentrations during prolonged exercise and reports of interference by FFA in other thyroid hormone assays. Apparent rT3 values increased by 19% and 34% in in vivo studies of acute lipolysis in subjects 5 min post exercise or 10 min post heparin, respectively, while T3 and T4 concentrations were unchanged. Varying concentrations of palmitic acid were added in vitro to four normal sera, and the increase in FFA concentration correlated significantly with the increase in apparent rT3 values. The mean +/- SE of the regression slope was 9.3 +/- 1.8 ng/dl rT3/mM FFA (r = 0.96 +/- 0.02). The addition of linoleic acid produced a similar effect. T3 and T4 concentrations were unchanged. The interaction of FFA in the rT3 RIA was unrelated to the procedure used to separate the assay, to the concentration of 8-anilino-1-napthalene-sulfonic acid in the assay buffer, to FFA binding directly to the antisera or to use of a particular antisera. The magnitude of the effect was similar in charcoal-treated sera, and the addition of 2 mM palmitic acid to the assay standard curve decreased the y intercept but did not alter the slope, suggesting an interaction of rT3 with FFA, rather than change in affinity of the antisera.

The impact of varying caloric intake on peripheral monodeiodination and plasma disposal of T3, rT3, and the three diiodothyronines (T2) was studied in five normal subjects while they were consuming a low calorie diet (1200 Cal/day) and again while receiving a high calorie diet (3600 Cal/day). Toward the end of each diet period 240 nmol 3,3'-T2 (126 micrograms) and 80 nmol 3',5'-T2 (42 micrograms) were infused for 7 h, and a bolus injection of 137 nmol 3,5-T2 (72 micrograms) was followed by a 12-h infusion of 69 nmol 3,5-T2 (36 micrograms) and 111 nmol rT3 (72 micrograms) on another day. [125I]T3 (30 muCi) was injected on the third day. The T2 and rT3 concentrations were measured by RIA during the 2 days of infusion, and the serum disappearance of [125I]T3 was studied by immunoprecipitation and trichloroacetic acid precipitation of the labeled T3. Four to 5% of the plasma disposal of T3 was accounted for by 3'-monodeiodination, and 36-39% by 5-monodeiodination. Increasing caloric intake resulted in a higher overall plasma disposal rate of T3, but no change in the percentage of T3 metabolized by monodeiodination pathways. In contrast, 5'-monodeiodination accounted for 21% of the total plasma disposal of rT3 during the low calorie diet and 45% during the high calorie intake. This increase in 5'-monodeiodination of rT3 was at the expense of alternative pathways of disposal. A marked increase in the plasma clearance rate of 3,5-T2 was also found during the high calorie diet, indicating that the level of caloric intake affects pathways of metabolism other than outer ring monodeiodination. These studies emphasize the important role played by diet in the regulation of peripheral thyroid hormone metabolism through modulating outer ring monodeiodination, and that overnutrition changes other pathways of iodothyronine metabolism as well.

Two experiments were conducted to determine if variations in diet composition sufficient to alter circulating triiodothyronine (T3) concentration would influence hepatic mitochondrial metabolism. In experiment 1, mitochondrial respiration and the activity of succinate dehydrogenase (SDH), cytochrome oxidase (CO) and alpha glycerophosphate dehydrogenase (m alpha-GPD) were measured in 42-day-old male rats fed diets containing casein/carbohydrate/fat: 8/73/10% (low protein), 22/59/10% (control protein), and 45/36/10% (high protein) for 3 weeks. When compared to control, serum T3 was increased 2-3 times in the low and decreased 19% in the high protein-fed groups. Mitochondria isolated from low protein-fed rats consumed less oxygen in both state 4 and state 3 with succinate as substrate when compared to control or high protein fed rats. However, ADP/O and respiratory control (RC) ratios were similar in all groups. Activity of SDH and CO was decreased only in low protein-fed rats. M alpha-GPD activity was increased in the low and decreased in the high protein fed-rats. In experiment 2, alpha-glycerophosphate shuttle activity was increased 2-3 fold and malate-aspartate shuttle activity decreased 60% in intact mitochondria isolated from low protein-fed rats when compared to rats pair-fed control diet. These results suggest a role for diet composition as a regulator of hepatic intermediary metabolism mediated by thyroid hormones.

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.

Aerobic exercise in addition to severe caloric restriction was studied for its effects on resting energy expenditure (REE), weight loss, and lean tissue preservation in adult women. A formula diet providing 1.5 g protein and 0.5 g carbohydrate (CHO) per kilogram of ideal body weight daily (mean intake 720 kcal/d) was given to 12 overweight inpatients for 4 to 5 weeks. Six subjects remained sedentary (group 1), while the other six subjects (group 2) performed supervised endurance exercise (a total of 27 hours at 50% of maximal oxygen uptake (VO2max) over 4 weeks). Lean tissue preservation was excellent in both groups and was unaffected by the group 2 exercise regimen. Weight loss over 4 weeks in the two groups did not differ (group 1, 6.9 +/- 0.7 kg; group 2, 6.5 +/- 0.7 kg). The VO2max was not increased after 4 weeks of exercise compared with controls. The resting oxygen consumption (rVO2) of both groups declined 10% (P less than .001) in the first seven days of dieting. Thereafter the rVO2 in group 1 remained stable, but a further 17% reduction occurred in group 2 (P less than .03) by the third week of exercise. The free triiodothyronine (fT3) concentration also fell more in group 2 (P less than .05), suggesting a relationship between fT3 and energy expenditure during severe caloric restriction. The ergometer exercise for up to two hours daily was well tolerated. The absence of either a training effect or accelerated weight loss in group 2 may be due to the limited duration (4 weeks) or intensity of the exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.

The thermic effect of infused glucose and insulin was measured by combining the hyperinsulinemic euglycemic clamp technique with indirect calorimetry, in 10 normal weight volunteers (group I), 7 obese subjects with normal glucose tolerance (group II), and 13 obese subjects with abnormal glucose tolerance or noninsulin-dependent diabetes mellitus before (group IIIa) and after weight loss of 10.8 +/- 0.4 kg (group IIIb). During hyperinsulinemia (760-1,100 pmol/liter), total glucose disposal from combined endogenous production and glucose infusion was 545 +/- 49, 441 +/- 70, 233 +/- 35, 231 +/- 31 mg/min and energy expenditure changed by + 0.476 +/- 0.080, +0.293 +/- 0.095, -0.114 +/- 0.063, and +0.135 +/- 0.082 kJ/min in group I, II, IIIa, and IIIb, respectively. The increased energy expenditure correlated with glucose storage (measured cost of processing the glucose: 1.33 kJ/g). In group IIIa there was no increase in energy expenditure in response to glucose and insulin infusions. After therapy (group IIIb) there was a significant recovery (P less than 0.05) of the thermic effect of infused glucose although total glucose disposal was unchanged. It is proposed that the recovered thermic effect of infused insulin/glucose is due to the different contributions of gluconeogenesis in the fasting state and during the glucose clamp before and after weight loss. In addition we hypothesize that some of the lower thermic effect of food reported in obese noninsulin-dependent diabetics may be explained by decreased energy expenditure due to a greater suppression of hepatic gluconeogenesis as well as by lower storage rate.

Thyroid hormones have a direct effect on the basal or resting metabolic rate in man and a permissive effect on the adaptive thermogenesis of small animals, while altering the energy expended in exercise to the extent that patients with thyroid disorders exercise to a greater or lesser degree. The physiological concepts of energy expenditure need to be seen in the context of a new method for measuring 'thyroid thermogenesis'. Thyroid hormones seem, in evolutionary terms, to have developed a thermogenic role during the transition from poikilothermy to homeothermy; they are responsible for the increased heat production required for homeotherms to maintain body temperature above that of the environment. The potential mechanisms responsible for thyroid hormone-controlled energy expenditure are complex. Uncoupled oxidative phosphorylation is probably not responsible for thyroid hormone-controlled thermogenesis except in the special case of brown adipose tissue thermogenesis, where thyroid hormones act permissively. The concept that increased ATP generation must be coupled to ATP utilization needs to be linked with the idea that thyroid hormone-controlled thermogenesis must be through inefficient pathways of metabolism. Several of these potentially important pathways of intermediary metabolism in thyroid hormone-controlled thermogenesis can now be defined and measured, but their role in the regulation of nutritionally induced alterations in thyroid status and thermogenesis remains to be explored.

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 less than 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 less than 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P less than 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.

The characteristics of regional brown (BAT) and white adipose tissue (WAT) growth and of thermogenesis following experimental overfeeding were studied in groups of male Sprague-Dawley rats fed lab chow or cafeteria diets for 8 weeks postweaning. Regional BAT and WAT growth was determined by dissection and weighing, and thermogenesis was characterized by measurements of resting and norepinephrine (NE)-stimulated oxygen consumption, of serum thyroid hormone concentrations, and of 24-hour urinary NE excretion levels. Cafeteria feeding resulted in a 113% increase in total BAT, with the most prominent increases in the interscapular, thoracic, and perirenal regions. Retroperitoneal, epididymal, and omental WAT were significantly greater in cafeteria than in chow-fed rats. Resting oxygen consumption of cafeteria-fed rads increased by 10% and NE excretion by 64% compared to chow-fed controls, while serum T3 concentrations were nearly doubled in the cafeteria-fed rats. The thermogenic response to NE injection in cafeteria-fed rats was 102% of their resting levels, compared to a 51% increase in the chow-fed controls. The results indicate that increased BAT growth occurs in all primary BAT depots following cafeteria-feeding in rats, and that the greater BAT mass is qualitatively proportional to their greater capacity for non-shivering thermogenesis. Also, the increased NE excretion and greater serum T3 concentration are consistent with increased sympathetic and thyroidal activity and may in part explain the thermogenic response to diet in the rat.