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Overfeeding normal volunteers with either carbohydrate or a mixture of supplements for 20 days increased resting metabolic rate, but most of the excess energy was retained. There was no significant increase in urinary VMA or catecholamine excretion or plasma catecholamine concentrations during overfeeding, suggesting that there was no diffuse activation of the sympathetic nervous system. Overfeeding did not enhance the thermogenic response to norepinephrine infusion, suggesting that the increase in resting metabolic rate during overfeeding in man is not mediated by increased sensitivity to norepinephrine or by hypertrophy of brown fat. Propranolol slightly reduced postprandial resting metabolic rate during overfeeding is not mediated by increased sympathetic nervous system activity. These data are not consistent with the hypothesis that the sympathetic nervous system regulates dietary thermogenesis in man.

The increase in energy expenditure after intake of 100 g of glucose (thermic effect of glucose), was studied in 11 lean and 13 obese women. Before glucose ingestion, resting metabolic rate, uncorrected for weight or surface area, was 15% higher in the obese subjects than in the lean subjects, but there was no difference between groups in the thermic effect of glucose. The obese subjects were hyperinsulinemic relative to the lean subjects, but the area under their glucose response curves was normal. The increase in norepinephrine levels associated with glucose intake was the same in the obese and lean groups. The magnitude of the thermic effect of glucose was not correlated with the increase in plasma norepinephrine levels, plasma insulin levels, or pulse rate, or with body weight, age or body mass index. Resting metabolic rate did not significantly increase in 10 subjects given a noncaloric control solution. These data show that obese subjects with normal glucose tolerance have a normal thermic response to glucose.

Hypothermia in humans during insulin-induced glucopenia has been largely attributed to impaired heat production. To further study the mechanism for hypothermia during glucoprivation six normal males were given 20-min intravenous infusions of 2-deoxy-D-glucose (2-DG), 50 mg/kg, a competitive inhibitor of glucose utilization. Oxygen and carbon dioxide exchange was measured to determine heat production by indirect calorimetry. Decreases in core temperature were initially associated with activation of mechanisms for heat loss such as sweating and hyperpnea 30-120 min after 2-DG infusion. Hypothermia persisted in spite of markedly increased plasma catecholamine, glucose, and free fatty acid levels from 60 to 180 min and increased heat production from 120 to 180 min after 2-DG infusion. Thus in contrast to the proposed mechanism for insulin-induced hypothermia, the hypothermia of 2-DG-induced glucoprivation is a consequence of increased heat loss and not of decreased heat production.

The thermic effects of 400 kcal meals of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) were compared in seven healthy men. Metabolic rate was measured before the meals and for 6 h after the meals by indirect calorimetry. Mean postprandial oxygen consumption was 12% higher than basal oxygen consumption after the MCT meal but was only 4% higher than the basal oxygen consumption after the LCT meal. There was a 25-fold increase in plasma beta-hydroxybutyrate concentration and a slight increase in serum insulin concentration after MCT ingestion but not after LCT ingestion. Plasma triglyceride concentrations increased 68% after the LCT meal and did not change after the MCT meal. These data raise the possibility that long-term substitution of MCT for LCT would produce weight loss if energy intake remained constant.

Glucoprivic stress induced by 2-DG (2-deoxy-D-glucose) is associated with increased oxygen consumption (thermogenesis) and sympathetic nervous system activity, as well as elevations of circulating levels of various hormones and metabolic substrates. To examine the role of beta-adrenergic stimulation in the thermogenic, hyperglycemic, and lipolytic responses to glucoprivation, we administered intravenous infusions of propranolol or normal saline (placebo) during 2-DG challenges in seven healthy males. 2-DG alone produced large increments in plasma catecholamine levels, hyperglycemia, a 3.5-fold increase in plasma free fatty acid (FFA) levels, a 15 beat/min increase in pulse rate, and hypothermia in spite of a 20% increase in oxygen consumption. When propranolol was given, 2-DG produced only a 50% increase in FFA levels, no change in oxygen consumption, and a 17 beat/min fall in pulse rate associated with a 25% increase in mean arterial blood pressure. Propranolol only slightly attenuated the hyperglycemia and hypothermia associated with 2-DG but potentiated the elevations of plasma epinephrine levels. It is concluded that 2-DG-induced thermogenesis and lipolysis are primarily dependent on beta-adrenergic stimulation.

Noradrenergic central and peripheral nervous system mechanisms for the control of food intake and thermogenesis, respectively, have been described in rats and, to a lesser extent, in humans. To examine further the role of the sympathetic nervous system in energy balance modulation during glucoprivation, the alpha 2-adrenoreceptor agonist clonidine was given to subjects receiving 2-deoxy-D-glucose, a competitive inhibitor of glucose utilization, which induces sympathetic discharge, ingestive behavior, and thermogenesis by initial actions in the central nervous system. Increases in food intake and thermogenesis in association with activation of descending sympathetic outflow during 2-deoxy-D-glucose-induced glucoprivation were totally abolished by clonidine administration. Neither increases in hunger ratings after 2-deoxy-D-glucose infusions nor basal hunger and food intake after sham infusions were decreased by clonidine treatment, which nevertheless reduced thermogenesis under basal conditions. These results clearly indicate that catecholamine-mediated thermogenesis under both stimulated and basal conditions is inhibited by central or peripheral actions of clonidine, presumably at the level of alpha 2-adrenoreceptors. The reduction in food intake brought about by clonidine treatment in subjects undergoing glucoprivic stress may be the result of potentiation of satiation or reduction of hunger during a test meal rather than decreased hunger before a test meal.

The effect of the beta-adrenergic antagonist propranolol on the increase in resting metabolic rate (RMR) induced by overfeeding was examined to determine whether increased beta-adrenergic activity contributes to this response. Six male subjects who were overfed with carbohydrate (1,600 excess kcal/day) for 10 days without drug treatment (control group) had increases (compared with values after 10 days of weight maintenance) in RMR after 6 days [0.24 +/- 0.06 kcal/min (22%)] and 10 days of overfeeding [0.17 +/- 0.03 kcal/min (15%)]. Eight male subjects were given a weight-maintenance diet for 10 days with oral propranolol treatment (40-60 mg every 6 h) over the last 7 days of this period. Five of these subjects were then overfed for 10 days, and three remained on the weight-maintenance diet; propranolol treatment continued until the end of the study. Propranolol significantly reduced RMR (mean 9%) before the onset of overfeeding but did not prevent increases in RMR after 6 days [0.18 +/- 0.05 kcal/min (16%)] and 10 days of overfeeding [0.17 +/- 0.03 kcal/min (15%)]. In the subjects who remained on the weight-maintenance diet throughout the study, there was no reversal of propranolol's initial reduction of RMR that would have falsely elevated the overfeeding effect. These data provide further evidence that the increase in RMR induced by overfeeding in humans is not mediated by increased beta-adrenergic activity.

Daily carbohydrate intake of seven men with normal weight was limited to 220-265 g/d for 6 d and then increased to 620-770 g/d for 20 d, while intake of protein, fat, and sodium remained constant. Carbohydrate overfeeding increased body weight by 4.8%, basal oxygen consumption (VO2) by 7.4%, BMR by 11.5%, and serum triiodothyronine levels by 32%. Overfeeding did not affect the thermic effect of a standard meal. Intravenous propranolol reduced the thermic effect of a meal by 22% during the base-line feeding period, and by 13% during carbohydrate overfeeding, but did not affect preprandial VO2. Overfeeding attenuated the rise in plasma glucose and FFA levels induced by infusion of norepinephrine, but had no effect on the increase in VO2 induced by norepinephrine. Overfeeding did not alter 24-h urinary excretion of vanillylmandelic acid, supine plasma catecholamine levels (pre- and postprandial), blood pressure, or plasma renin activity, but increased peak standing plasma norepinephrine levels by 45% and resting pulse rate by 9%. Even though short-term carbohydrate overfeeding may produce modest stimulation of sympathetic nervous system activity in man, the increase in thermogenesis induced by such overfeeding is neither suppressed by beta adrenergic blockade nor accompanied by an increased sensitivity to the thermogenic effects of norepinephrine. These data do not support an important role for the sympathetic nervous system in mediating the thermogenic response to carbohydrate overfeeding.