Koichi Arase

Feeding and hyperglycemia induced by 1,5-anhydroglucitol in the rat

Abstract 1,5-Anhydroglucitol (1DG, minus an oxygen on carbon 1 of the glucose molecule), has been known physiologically to be present in human cerebrospinal fluid. In order to clarify direct evidence concerning 1DG-induced feeding, hyperglycemia and adrenomedullary mediation of hyperglycemia, 1DG was infused into rat lateral ventricle in doses of 11.8, 21.0, 33.7 and 50.0 μmoles/rat, and its effects compared to those of 2-deoxy-D-glucose (2DG). A dose-dependent increase in food intake after 1DG was 1/3.4 to 1/10.6 of that produced by equimolar 2DG. After 1DG serum glucose concentration gradually increased, peaked at 30 min, and subsequently decreased. Hyperglycemia induced by 1DG was 1/2.1 to 1/2.2 of that produced by 2 DG and was reduced 81% following adrenomedullectomy, which was close to the value for 2DG: 80%. Results were consistent with known differences in the biochemical actions of 1DG and 2DG at the level of substrate specificity of the hexokinase and the rate of glucose transport. These actions suggest that 1DG could provide physiological signals for food intake.

Theophylline disrupts diurnal rhythms of humoral factors with loss of meal cyclicity

To test the possibility that theophylline induced circadian disappearance of food intake might depend upon rhythmic disruption of blood glucose, insulin and free fatty acids (FFA), theophylline was administered chronically. This markedly lengthened postprandial intermeal intervals during the dark, and induced approximately identical intermeal intervals and identical meal sizes in the light and dark periods. In contrast to the clear light-dark dependent oscillations of serum glucose, insulin and FFA in the controls, the theophyllinized rats lost circadian fluctuation of each of these three chemical substances. Further, theophyllinized rats, unlike controls, had no time-dependent fluctuation in the levels of these substances at -120, -60 or -15 min preceding the onset of the first meal before the dark. These findings, together with previous reports, explain the disappearance of nocturnal feeding rhythm in theophyllinized rats in terms of functional destruction of circadian regulation in the hypothalamus which modulate the production of chemical determinants of food intake.

1-deoxy-glucosamine initiates, then effectively suppresses feeding in the rat

The deoxy analogues of D-glucose, 1-deoxy-D-glucosamine and D-glucosamine, are biochemically and structurally similar to 1-deoxy-D-glucose, so their direct effects on food intake were studied. Both 12 and 24 mumol 1-deoxy-glucosamine potently decreased feeding and body weight after an initial transient elicitation of food intake. The suppression included decreased meal size and prolonged postprandial intermeal interval which persisted for at least 3 days after injection. Ambulatory activity was unaffected. The initial elicitation of feeding was not accompanied by drinking episodes, and subsequent drinking suppression was persisted. These findings, plus other biochemical evidence, suggest that inversion with an amino group or removal of a hydroxyl group from C-2 and/or C-1 may affect feeding.

Administration of D-glucosamine into the third cerebroventricle induced feeding accompanied by hyperglycemia in rats.

D-glucosamine, 2-amino-2-deoxy-D-glucose, is known to be an endogenous glucose analogue and to antagonize glucose uptake and metabolism. The present experiments were aimed to clarify effects of glucosamine and related chemical substances on ingestive behavior, as well as its direct effects on hypothalamic neurons. Infusion of 24 mumole glucosamine into the third cerebroventricle induced feeding within 30 min in 5 rats out of 7 tested, accompanied by increased ambulatory activity. No periprandial drinking was observed. Plasma glucose level increased, peaking at 30 min after the injection. Plasma insulin level tended to increase, but not significantly. Electrophoretic application of glucosamine activated glucose-sensitive neurons in the lateral hypothalamus and suppressed glucoreceptors in the ventromedial hypothalamus. These facts, together with other reported results, suggest that glucosamine can modulate physiological feeding and that carbon 2 of the glucose molecule is important in feeding modulation by glucose analogues.

Circadian pattern of stress response to affective cues of foot shock

Abstract Formation of gastric lesions, changes in body weight and changes in serum level of endogenous chemical substances in response to stressful stimuli were studied. To examine the influences of stressful events on bodily responses, the stimuli were introduced in the terms of affective communication by using a communication box. The “Sender” received physical stimuli of electric foot shocks and the “Responder” received affective information such as visual, auditory, and olfactory cues from “Sender” with no exposure to foot shock. The “Responder” exhibited significantly more severe gastric lesions than the “Sender.” The degree of susceptibility to the formation of gastric lesions and weight reduction increased when the stimuli were administered during the dark cycle. Changes in the level of endogenous chemical substances were not significant. The results indicated that a circadian rhythm can be detected in susceptibility to gastric lesions in response to indirect stimulus cues.

Short-chain polyhydroxymonocarboxylic acids as physiological signals for food intake

In order to clarify the effects of endogenous organic acids on short and long-term feeding behavior, ingestive behavior was monitored for 2 hr before and after intra-third ventricular infusions of 3,4-dihydroxybutyric acid (2-deoxytetronic acid, 2-DTA), 2,4,5-trihydroxypentanoic acid (3-deoxypentonic acid, 3-DPA), and 3-hydroxybutyric acid (3-HBA). In addition, meal patterns were recorded for 2 days before and after the ventricular infusions. 2-DTA suppressed both short and long-term feeding by decreasing meal size (MS). 3-DPA elicited transient feeding behavior, but caused no change in long-term feeding. 3-HBA initially stimulated feeding, but subsequently suppressed long-term feeding by decreasing MS and prolonging postprandial intermeal interval (IMI). The suppressive effects of 3-HBA on feeding behavior lasted about 24 hr longer than those of 2-DTA. Based upon these observations as well as our previous reports, it appears that some of the processes affecting hunger and satiation are mediated by changes in central and peripheral concentrations of these organic acids.

Feeding suppression induced by intra-ventricle III infusion of 1,5-anhydroglucitol

1,5-Anhydroglucitol (1-DG) has been known as an antimetabolic glucose analogue. Using gas chromatography, 1-DG was found to be physiologically present in rat serum. In order to investigate its direct and long-term effects on feeding, 1-DG was infused during the light period into the rat third ventricle in doses of 3.0, 6.0 and 12.0 mumol/rat. Its effects were then compared to those of similarly applied 2-deoxy-D-glucose (2-DG). Following initial hyperphagia, both of these glucose-analogues produced suppressive effects on feeding during the subsequent day throughout the light and dark periods. On the third day after 2-DG injection reduction of feeding did not recover completely to the pretreatment baseline levels, but it did recover after 1-DG. Both 1-DG and 2-DG caused linear dose-related hypophagia, with the slope for 1-DG being about half of that for 2-DG. It is suggested that the delayed hypophagia which followed the initial hyperphagia produced by deoxyglucose was a result of sustained inactivation of the Na-pump due to intracellular ATP deficiency caused by accumulation of deoxy-glucose-6-phosphate.

Structural characteristics of endogenous sugar acids and relations to feeding modulation.

Structural specificity among short-chain organic acids for effects on feeding behavior, blood glucose and insulin was investigated by infusion of 1 exogenous and 6 endogenous derivatives into the rat third cerebral ventricle. Glyceric acid (GEA) (1.0 mumol), 3,4-dihydroxybutanoic acid gamma-lactone (3,4-DB) and 3,4,5-trihydroxypentanoic acid gamma-lactone (3,4,5-TP) (2.50 mumol) decreased food intake for, at most, 24 h. These acids depressed the size of the first meal after infusion, but did not affect latency to the first meal, eating speed, drinking or ambulation. Infusion of 2,4-dihydroxybutanoic acid gamma-lactone (2,4-DB) (1.25 mumol), 2,4,5-trihydroxypentanoic acid gamma-lactone (2,4,5-TP), and an exogenous compound, 2,4,5,6-tetrahydroxyhexanoic acid gamma-lactone (2,4,5,6-TH) (2.50 mumol), induced transient initial feeding which was not necessarily accompanied by periprandial drinking. Ambulation was concomitantly increased. Of these organic acids, 3,4-DB and 2,4,5-TP were most potent in their effects on feeding. Hyperglycemia was induced by 2.50 mumol 3,4-DB leaving insulin unaffected; 2.50 mumol 2,4,5-TP caused hypoglycemia, with a persistent but not significant rise in insulin. The results suggest that slight structural differences of endogenous organic acids, in particular the positions of hydroxyl groups on the lactone ring of 4-butanolide, may be important in feeding modulation by conveying intrinsically reciprocal signals to neurons involved in feeding and satiety.

Effect of an amino group at carbon 2 of 1-deoxyglucose analogues on anorexia in the rat

A steric hindering group at carbon 2 of 1-deoxyglucose analogues was introduced by epimerization, deoxidation and substitution of a hydroxyl group with either an acetamido or a fluoro group. Injection of this analogue into the rat third cerebroventricle attenuated the feeding suppression produced by 1-deoxyglucose. In contrast, the replacement of a hydroxyl group at carbon 2 with an amino group produced anorexia of the same magnitude as that produced by 1-deoxyglucose. Amination at carbon 2 was more potent than that at carbon 3, 4 or 6. These results indicate that an amino group at carbon 2 of the glucose molecule is important to reinforce the feeding suppression caused by 1-deoxyglucose analogues.