Dean A. Thompson

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.

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.

Increased hunger and thirst during glucoprivation in humans.

Abstract Five male volunteers received two intravenous infusions of 2-deoxy-D-glucose (2DG) and one of normal saline. Hunger and thirst ratings, solid-food and water intake, and plasma epinephrine and glucose levels were greater after both of the 2DG infusions than after the saline infusion. This study suggests that the increase in water intake caused by 2DG does not depend on elevated hunger, and demonstrates that increased caloric intake after 2DG infusions is not dependent on greater thirst. Behavioral and adrenomedullary responses to both 2DG infusions were qualitatively and quantitatively the same, suggesting that there are no residual effects of 2DG that diminish the ability of the subjects to respond to glucoprivation. Measurements of possible thirst stimuli revealed no clear mechanism for the dipsogenic effect of 2DG.

Increased Thirst and Plasma Arginine Vasopressin Levels during 2-Deoxy-d-glucose-induced Glucoprivation in Humans

Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central nervous system glucoprivation were investigated by administering 20-min i.v. infusions of 2-deoxy-d-glucose (50 mg/kg), a competitive inhibitor of glucose utilization, or normal saline (sham), to 24 normal volunteers. Some of the infusions were administered in combination with neuropharmacological blocking agents (placebo). The behavioral, physiological, metabolic, and hormonal correlates of 2-deoxy-d-glucose (2DG)-induced gluco-privation and AVP secretion were studied in a group (n = 5) pretreated for 1 wk with either mazindol (1 mg per os three times per day), a potent norepinephrine and dopamine-reuptake blocker, or placebo. A second group (n = 5) received either propranolol (3 mg/3 min followed by 80 mug/min) or normal saline infusion before and during 2DG administration. With 2DG alone, plasma AVP levels increased from 1.3+/-0.3 pg/ml at base line to a peak of 4.5+/-1.4 pg/ml at 60 min and remained elevated for 150 min. From 30 to 180 min after 2DG administration, the 2DG-infused volunteers increased their water intake in comparison with sham-infused volunteers. Marked increases in epinephrine and slight increases in norepinephrine were associated with increases in plasma glucose and renin activity and decreases in plasma potassium. Plasma sodium and osmolality increased transiently and mean arterial pressure (MAP) fell. These changes, however, were small and inconstant and could not account for the observed increases in thirst and AVP levels. Pretreatment with mazindol prevented the decrease in MAP and the increase in plasma renin activity (PRA) following 2DG infusions without modifying increased thirst, water intake, or AVP responses to glucoprivation. Pretreatment with propranolol effectively blocked beta-adrenoreceptors as evidenced by increased MAP and plasma epinephrine, and abolition of the RPA increases during 2DG-induced glycoprivation, but did not suppress AVP and thirst responses. A cervical cord-sectioned patient lacking descending sympathetic out-flow had a potentiated thirst response to 2DG-induced glucoprivation in the absence of increases in sodium, catecholamines, and PRA. Thus 2DG administration activates mechanisms for increased thirst and AVP which are unrelated to changes in peripheral catecholamines, MAP, PRA, and osmolality.

Plasma dihydroxyphenylglycol (DHPG) in the in vivo assessment of human neuronal norepinephrine metabolism.

We investigated the utility of deaminated norepinephrine (NE) metabolites in the study of human sympathetic nervous pathophysiology. Plasma levels of the NE metabolite dihydroxyphenylglycol (DHPG) appear to be related to intraneuronal NE stores. Plasma DHPG increases when sympathetic nervous activity or circulating NE increase and decreases when neuronal NE is depleted or neuronal NE reuptake is blocked. Changes in plasma dihydroxymandelic acid (DOMA) related less closely to changes in plasma NE. The coupling of measurements of plasma NE with its deaminated metabolites and DHPG may improve understanding of human NE metabolism and neuronal NE reuptake.

Effects of 2-deoxy-D-glucose on food and water intake and body temperature in rats

Comparisons between early daytime and early nighttime effects of 2-deoxy-D-glucose (2DG) injections on food and water intake and rectal temperature were made. Food intake was significantly enhanced by 2DG injections regardless of the phase of the light cycle. In the daytime, water intake was increased by a lower dose of 2DG (200 mg/kg, IP) but there was no further increase at a higher dose (400 mg/kg). At night, the lower dose of 2DG had no effect on water intake but the higher dose suppressed the water intake normally associated with feeding. Administration of 2DG reduced preprandial rectal temperature in a dose dependent fashion in both phases of the light cycle. However, preprandial rectal temperatures were decreased more at night than during the daytime after injection of the higher dose of 2DG. Therefore, 2DG-induced hypothermia is dependent on both the dose of 2DG injected and the phase of the light cycle in which glucoprivation is produced. Furthermore, below a certain level of body temperature, rats markedly reduced drinking behavior while maintaining but not increasing their feeding response to 2DG-induced glucoprivation. These results suggest that behaviors may be directed toward preservations of body temperature in preference to relief of hunger by eating and of thirst by drinking.

Evidence That Receptors Controlling Growth Hormone and Hyperglycemic Responses to Glucoprivation are Located in the Hindbrain

Infusions of the glucose analogue 5-thioglucose (5TG) were performed either in the lateral or fourth ventricle in animals having a patent or blocked cerebral aqueduct in order to determine the location of glucoreceptor(s) responsible for the hyperglycemic and growth hormone (rGH) responses to glucoprivation. Infusion of 5TG in the fourth ventricle induced hyperglycemia and a decrease in rGH levels whether or not the aqueduct was patent. Infusion of 5TG in the lateral ventricle produced the hyperglycemic response without decreasing rGH in animals with the aqueduct patent whereas both responses were abolished in animals with the aqueduct blocked. These results indicate that glucoreceptors that mediate hyperglycemia and a decrease in rGH in response to cerebral glucoprivation are located in the hindbrain.

Pharmacological evidence for opioid and adrenergic mechanisms controlling growth hormone, prolactin, pancreatic polypeptide, and catecholamine levels in humans☆

A group of 14 healthy subjects received 50 mg/kg body weight of 2 deoxy-D-glucose (2DG) IV in a 20-minute infusion to induce glucoprivation and stimulate the release of growth hormone (GH), prolactin (PRL), pancreatic polypeptide (hPP), and catecholamines. Six subjects having spontaneously high GH baseline levels (greater than 8 ng/mL) failed to mount a GH response to 2DG-induced glucoprivation while eight subjects having low GH baseline levels (less than 8 ng/mL) all had increases (greater than 10 ng/mL) of GH levels after 2DG (P less than 0.05). Baseline level of GH was a reliable predictor of subsequent GH response to 2DG. Administration of the alpha 2-adrenoreceptor agonist clonidine (0.5 mg po) reliably increased GH levels (P less than 0.05). Elevated GH levels following clonidine administration abolished GH responses to subsequently infused 2DG (P less than 0.05). While these data do not exclude the possibility of a short loop feedback control of GH secretion, they strongly suggest that the direction of the GH response to a provocative stimulus is determined by the antecedent GH level and that an alpha-adrenoreceptor mechanism is involved in such a biphasic modulation of GH levels. Clonidine administration significantly reduced total catecholamine, pancreatic polypeptide, and prolactin response to 2DG while opiate receptor blockade with naloxone (10 mg IV bolus followed by 2 mg/hr) did not affect catecholamine and pancreatic polypeptide response but did slightly attenuate the GH and PRL response to glucoprivation. We conclude that alpha adrenoreceptor mechanisms are of major importance while opiate receptor mechanisms are of relatively minor importance in modulating the effects of glucoprivation on sympathetic outflow and hPP, GH, and PRL levels.

Suppression of prolactin and growth hormone responses to 2-deoxy-D-glucose-induced glucoprivation by mazindol in humans.

Glucoprivation induced by 2-deoxy-D-glucose (2DG) 20 min infusions (50 mg/kg) increases growth hormone (GH) and prolactin (PRL) levels in humans. To determine if mazindol, a potent dopamine (DA) and norepinephrine (NE) reuptake blocking agent, might affect basal and stimulated GH and PRL levels in healthy male and female volunteers, mazindol (1 mg, TID,po) or placebo were administered for one week before 2DG infusions. Plasma samples for glucose, epinephrine (E), NE, PRL, and GH were collected before and after 2DG infusions. During placebo and mazindol therapy, basal values (ng/ml) did not differ for either PRL (8.8 +/- 1.6 versus 8.9 +/- 1.5 in females and 8.3 +/- 0.9 versus 7.7 +/- 0.6 in males) or GH (1.6 versus 1.7 +/- 0.1 in males and 6.6 +/- 3.3 versus 7.0 +/- 2.6 in females). Peak stimulated PRL levels were greater in females than in males (97.1 +/- 26.2 versus 21.4 +/- 5.3 ng/ml, p less than 0.05) while peak stimulated GH levels were greater in males than in females (28.2 +/- 1.7 versus 7.0 +/- 2.0 ng/ml, p less than 0.05). Mazindol therapy reduced 2DG-stimulated PRL responses (ng/ml) from 97.1 +/- 26.2 to 44.4 +/- 25.3 (p less than 0.0125) and from 21.4 +/- 5.3 to 13.6 +/- 3.4 (p less than 0.025) in females and males respectively, and GH responses (ng/ml) from 28.2 +/- 1.7 to 13.1 +/- 3.8 (p less than 0.05) and from 10.2 +/- 2.0 to 3.4 +/- 0.1 (p less than 0.05) in males and females respectively, but baseline PRL and GH levels were unaffected. A 50%-60% overall suppression of stimulated GH and PRL levels by mazindol was not significantly different between sexes and not consistently related to elevations in plasma glucose or E although stimulated plasma NE levels were higher during mazindol therapy.

Abnormal chromosome in Prader-Willi syndrome.

A Prader‐Willi Syndrome (PWS) patient was found to have an extra satellite chromosome, smaller than the normal Chromosome 22, in 60% of her metaphases. G‐ and C‐bandings showed that the extra chromosome did not derive from a Chromosome 15 as has been reported in some PWS patients. Because of variation in chromosomal abnormalities in the PWS patients reported, it was concluded that the chromosomal abnormalities found in them may be a secondary phenomenon rather than the cause of PWS.