Robert G. Campbell

Thermic effect of feeding in man: increased plasma norepinephrine levels following glucose but not protein or fat consumption.

In seven healthy male subjects, intake of 100 g protein hydrolysate produced significantly greater increments in energy expenditure than intake of 100 g glucose, 44 g fat, or a noncaloric control solution during the first 4 hr postcibum. Glucose and fat intake produced similar increments in energy expenditure. In contrast to the effects on thermogenesis, protein and fat intake did not alter sympathetic nervous system (SNS) activity, as estimated by plasma norepinephrine (NE) levels, whereas glucose intake significantly increased NE levels. Plasma levels of immunoreactive insulin were stimulated by glucose intake to a much greater level than by protein intake, and were unaffected by ingestion of the fat and control solutions. Pulse rate significantly increased following ingestion of all nutrients compared to pulse rate changes during the control test. These data support the traditional concept of a greater thermic effect of protein than of carbohydrate or fat, but the possibility of SNS involvement in the thermic effect of protein and fat is not supported.

Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans.

Because intravenous infusion of beta-hydroxybutyrate (beta-OHB) has been reported to decrease urinary nitrogen excretion, we investigated in vivo metabolism of leucine, an essential amino acid, using L-[1-13C]leucine as a tracer during beta-OHB infusion. Leucine flux during beta-OHB infusion did not differ from leucine flux during normal saline infusion in nine normal subjects, whereas leucine oxidation decreased 18-41% (mean = 30%) from 18.1 +/- 1.1 mumol.kg-1.h-1 (P less than 0.01), and incorporation of leucine into skeletal muscle protein increased 5-17% (mean = 10%) from 0.048 + 0.003%/h (P less than 0.02). Since blood pH during beta-OHB infusion was higher than the pH during saline infusion, we performed separate experiments to study the effect of increased blood pH on leucine kinetics by infusing sodium bicarbonate intravenously. Blood pH during sodium bicarbonate infusion was similar to that observed during the beta-OHB infusion, but bicarbonate infusion had no effect on leucine flux or leucine oxidation. We conclude that beta-OHB decreases leucine oxidation and promotes protein synthesis in human beings.

Increased plasma norepinephrine concentrations and metabolic rates following glucose ingestion in man

The effects of glucose ingestion on plasma levels of norepinephrine (NE), epinphrine (E), immunoreactive insulin (IRI), and glucose, and the resting metabolic rate (RMR) were examined in six normal males. Ingestion of the glucose (100 g) solution significantly increased all of these measures except E levels, compared with changes observed during a control experiment in which an equal volume of water was ingested. The initial (0-60 min) increase in plasma NE levels and the increase in the RMR following glucose was significantly greater than the smaller increases that occurred during the control experiment. Plasma IRI and glucose levels peaked 30-60 min after glucose consumption, then declined toward basal values. These data show that glucose intake causes an elevation of the RMR and sympathetic nervous system activity greater than that caused by other aspects of the testing solution, and are consistent with the possibility that the increase in RMR following glucose ingestion is related to elevated sympathetic nervous system activity.

Stimulation of thermogenesis by carbohydrate overfeeding. Evidence against sympathetic nervous system mediation.

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.

Neural Control of Counter-Regulatory Events during Glucopenia in Man

The effect of autonomic denervation on the metabolic and hormonal responses during intracellular glucopenia in man was investigated. 2-Deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was administered intravenously to nine normal volunteers and to five patients, three with complete cervical cord transection (C-6) and two with idiopathic orthostatic hypotension. Before, during, and after a 20 min infusion of 2 DG (50 mg/kg) plasma concentrations of glucose, lactate, FFA, total catecholamines, immunoreactive insulin (IRI), human growth hormone (HGH), and cortisol were determined for periods up to 150 min. In control subjects, the initial elevation of FFA, glucose. HGH, and cortisol corresponded with the rise in total catecholamines, with maximal levels attained at 60 min, lactate rose at a slower rate, reaching peak levels at 150 min: although no change in IRI was noted. In contrast, 2 DG-induced glucopenic stress in the autonomic denervated subjects was characterized by no detectable catecholamine release or significant rise in glucose, FFA, lactate, or IRI. However, HGH and cortisol responses in four of the five patients were of a similar or greater magnitude than controls.These studies demonstrate that the integrity of the sympathoadrenomedullary axis is essential for the counter-regulatory response to intracellular glucopenia in man. Cortisol and HGH have no apparent role in these events.

Decrease in Resting Metabolic Rate During Rapid Weight Loss Is Reversed by Low Dose Thyroid Hormone Treatment

In order to determine if reduced serum T3 concentrations contribute to the decrease in resting metabolic rate (RMR) during rapid weight loss, we administered T3 (30 micrograms/d) and T4 (100 micrograms/d) to obese subjects receiving a very low energy diet to reverse a decrease in serum thyroid hormone concentrations. During the first two weeks of weight loss, before thyroid hormone replacement, the mean RMR of five obese subjects declined to 86% of the baseline level as the mean serum T3 concentration decreased to 72% of the baseline level. Thyroid hormone replacement for one week, while the low energy diet continued, increased the mean RMR to 94% of the baseline level while increasing mean serum T3 and T4 concentrations to approximately 130% of the baseline level. A second week of thyroid treatment caused no further change in RMR. These data suggest that reduced serum T3 concentrations contribute to the decrease in RMR during rapid weight loss. However, the regimen of thyroid hormone replacement employed did not completely restore a normal RMR in obese subjects on a very low energy diet, in spite of elevating serum thyroid hormone concentrations slightly above weight-maintenance levels.

Taste and olfaction in human obesity.

Earlier studies have shown differences between normal weight and obese humans in responsivity to external and internal stimuli. This study shows that normal weight and obese subjects do not differ in hedonic response to sucrose (taste) and benzaldehyde (odor). However, a perceptual typing of individuals based upon hedonic response is possible for both gustatory and olfactory processes. Ratings of pleasantness for the sweet taste of sucrose appear to generalize to the food-related odor of bitter almonds. The method of magnitude estimation as applied to the study of taste and olfaction in man may reveal relationship between changes in internal state and hedonic behavior.

Counterregulatory Hormonal Responses to Rapid Glucose Lowering in Diabetic Man

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P < 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P < 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels. These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.

The effect of adrenergic blockade on glucose-induced thermogenesis

The effect of alpha, beta, or combined sympathetic blockade on the increase in energy expenditure and concentrations of norepinephrine, glucose, and insulin following oral intake of 100 g of glucose was studied in lean subjects. Alpha blockade with intravenous (IV) phentolamine (n = 5) infusion increased oxygen consumption after glucose ingestion but no more than it increased the oxygen consumption when no glucose was given. Beta blockade with IV propranolol (n = 13) and combined alpha and beta blockade (n = 6) did not affect basal metabolic rate or the increase in metabolic rate after glucose ingestion. Phentolamine or combined propranolol plus phentolamine administration markedly increased plasma norepinephrine concentrations. Basal glucose and insulin concentrations were not affected by any of the infused drugs. Glucose-stimulated insulin concentrations were unchanged by propranolol and combined blockade, whereas there was a trend (P = 0.07) toward an increased response to glucose during phentolamine administration. These data do not support a role for the sympathetic nervous system in the increase in metabolic rate following glucose ingestion. The increase in metabolic rate during phentolamine administration can be attributed to beta adrenergic stimulation.

Opiate receptor blockade in man reduces 2-deoxy-d-glucose-induced food intake but not hunger, thirst, and hypothermia

Opioid peptides may act as neuromodulators in the central nervous system to conserve energy stores and water in mammals. To examine this hypothesis in man, the effect of opiate receptor blockade with naloxone on the hunger, thirst, and hypothermic response to 2-deoxy-D-glucose-induced glucoprivic stress was assessed. Opiate receptor blockade decreased stress-induced food intake but did not reduce marked increases in hunger produced by glucoprivation. Naloxone infusions did not change the hypercortisolemic, polydipsic, hypothermic, and thermogenic response to 2-deoxy-D-glucose. While these results do not suggest a major role for a beta-endorphin modulation of stress-induced hunger, hypothermia and water conservation, the reduction of food intake could be due to augmented satiety, perhaps associated with retardation of gastric emptying during opiate receptor blockade.