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.

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.

Lichtman et al. report in this issue of the Journal 1 that a subgroup of obese subjects whom they identified as resistant to dieting have failed to lose weight because they eat more and exercise less than they think. Doubly labeled water was used to measure total energy expenditure for two weeks. This method allows the accurate (±5 percent) and noninvasive measurement of total energy expenditure in free-living subjects without their awareness of the actual measurement. In combination with measurement of the components of daily energy expenditure by indirect calorimetry and analysis of body composition, the doubly-labeled—water method can be used . . .

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.

In summary, nutritionally directed alterations in thyroid hormone metabolism appear to be adaptive and to serve important protective roles in the overall economy of the body. These adjustments to nutrition are found at practically every level of thyroid regulation, beginning in the CNS and ending with the final action of thyroid hormones in the nucleus of cells. The cellular actions of thyroid hormones modify, and are modified by, as yet poorly understood interrelationships with substrates and other hormones. The level and composition of the energy intake, including whether the organism is in energy balance, are important signals directing these hormonal adaptations.

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.

Continuous respiratory exchange measurements were performed in nine obese and eight lean women for 1 h before, 3 h during, and 1 h after the intravenous administration of a nutrient mixture infused at twice the postabsorptive resting energy expenditure (REE). This experiment was conducted without or with beta-adrenergic blockade (iv propranolol). Propranolol administration did not change the postabsorptive REE [i.e., 1.03 +/- 0.07 before vs. 1.01 +/- 0.02 kcal/min after administration in lean women and 1.16 +/- 0.04 vs. 1.15 +/- 0.03 kcal/min (NS) in obese women]. The mean overall thermogenic response expressed as a percentage of the infused energy was similar in both groups and was not significantly blunted after propranolol infusion [6.9 +/- 0.4 vs. 5.9 +/- 0.6% in the lean women and 7.5 +/- 0.5 vs. 7.1 +/- 0.6% (NS) in the obese women]. During beta-adrenergic blockade the rate of lipid oxidation decreased in the lean group but was unchanged in the obese group and the glycemic response to nutrient administration was significantly higher in both groups than without propranolol. It is concluded that beta-adrenergic blockade has no effect on REE and on intravenous nutrient-induced thermogenesis in both lean and obese women.

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 μg/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 < 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 < 0.05) but not in the obese subjects (2.7%, P=NS) and fell during underfeeding in the obese (−9.1%,P < 0.02). There was a logarithmic increment above baseline in VO2v plasma NE concentration during the NE infusions (r=0.75, P < 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.

The impact of the increased T3 production induced by overfeeding is likely to be lessened if overfeeding also decreases the free fraction of thyroid hormones. Therefore, we examined the effect of 17 to 20 days of carbohydrate overfeeding of five men on total serum T4 and T3 concentrations, the free fraction of these hormones, and serum concentrations of thyroid-hormone binding proteins, TBG, TBPA, and albumin. Total serum T4 concentrations were unchanged by overfeeding and total serum T3 concentrations increased 42%. However, the free fraction of both T4 and T3 decreased during the overfeeding period, so that free T3 concentrations increased only 21% and free T4 concentrations decreased 17%. There was an increase in serum concentrations of both TBG (12%) and TBPA (20%), but no change in the concentration of albumin. We conclude that there is an increase in free T3 concentrations during overfeeding, in spite of a decrease in the free fraction of T3. However, the physiological effects of this increase in free T3 concentrations may be diminished by the decrease in free T4 concentrations.

The acute administration of a beta receptor-stimulating agent profoundly affects insulin-mediated glucose metabolism; however, little is known about the impact of chronic beta receptor stimulation on glucose metabolism and insulin sensitivity. We therefore investigated the effect of the chronic administration of a beta-2-agonist, terbutaline sulfate (TS), on glucose metabolism in 7 healthy, normal-weight, male volunteers between the ages of 21 and 30 yr. Studies were performed using the euglycemic, hyperinsulinemic (1.0 mU/min · kg) clamp technique before and after the oral administration of 5 mg of TS three times a day for 1 and 2 wk. Basal endogenous glucose production (EGP) (2.54 ± 0.11 versus 2.64 ± 0.14 mg/min · kg) and basal glucose oxidation (1.87 ± 0.16 versus 2.0 ± 0.2 mg/ min · kg) were unchanged by the chronic administration of TS. However, insulin-stimulated total glucose metabolism increased by 29% (7.0 ± 0.47 versus 9.05 ± 0.67 mg/min · kg; P < 0.02). Insulin-stimulated, nonoxidative glucose disposal increased by 45% (3.62 ± 0.42 versus 5.26 ± 0.48 mg/min · kg; P < 0.01), while insulin-stimulated glucose oxidation did not change significantly (3.38 ± 0.15 versus 3.79 ± 0.22 mg/min · kg). EGP was completely suppressed under both conditions. Mean basal plasma insulin concentration (41 ± 9 versus 49 ± 15 pmol/L) and insulin clearance during the clamp procedure was unchanged (477 ± 45 versus 474 ± 37 ml/min · m2). We conclude that chronic beta receptor stimulation with TS improves insulin-stimulated glucose disposal in man, mostly by improving nonoxidative glucose disposal, i.e., “glucose storage.” Mechanisms explaining these findings have not yet been elucidated. We suggest that an adaptive response of the sympathetic nervous system plays a role in this phenomenon.

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.

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 mimic plasma T3 levels observed in a previous overfeeding study, six lean healthy men received replacement amounts of L-thyroxine (200 μg/d) to block endogenous thyroid hormone production while consuming their habitual diet. After 4 weeks equilibration on T4, L-triiodothyronine (T3) was given (45 μg/d) in addition to T4, to produce mild T3-thyrotoxicosis, for another 2 weeks. At the end of this period T3 was discontinued but the subjects continued to receive T4 for another 2 weeks. Resting metabolic rate, exercise efficiency, and the thermic effect of food were measured using a ventilated hood, open circuit indirect calorimeter at the end of each phase of the experiment. There was a significant increase in the resting metabolic rate of 6% (P<0.01) while the subjects were mildly T3-thyrotoxic. The increase in energy expenditure however, during exercise on a bicycle ergometer or following a 500 kcal liquid-formula meal remained unaltered in the same situation. Thus, mild T3-toxicosis does not alter the efficiency of exercise or the thermic effect of food. These results suggest that the increased plasma T3 levels, observed in overfeeding, could explain corresponding increases in resting metabolic rate but not changes in the efficiency of exercise or the utilization of food.

Strong support has been gathered for a defect in insulin-glucose-mediated thermogenesis in obese and particularly obese insulin-resistant and/or diabetic subjects compared to lean subjects. This defect appears to be reversible with weight loss and improved insulin sensitivity. The mechanism for this blunted thermogic response is directly related to the decreased glucose storage in the obese and obese diabetic subjects.

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.