Masataka Fukushima

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.

Circadian and long term variation of certain metabolites in fasted rat, implications☆

Abstract In order to clarify subtle metabolic changes and the time course of metabolic variations associated with the central mechanisms of feeding and satiety, serum obtained from fasted rats during various hunger stages was profiled using a gas chromatography-mass spectrometry-computer system. On the basis of this work, chronobiological changes in metabolites following fasting were also evaluated. It was found that sampling method was critically important for determining the levels of organic acids. Changes in the time course of these organic acids were mainly divided into two patterns: a progressive increase over long-term starvation and a transient increase at about 36 hr of starvation. The levels of free fatty acids, 3-hydroxybutyrate, 2-deoxytetronate and 3-deoxypentonate were elevated around twilight after 24 and 36 hr of fasting. It was concluded that these organic acids were probably the compounds which elicit feeding behavior.

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.

New inexpensive device for estimating dry food intake in small animals

Abstract A new economical and compact device for measuring dry food intake in rats is described. The apparatus consists of a spill-proof feeding box with a slotted space on a front panel, through which a rat is allowed to feed, and a feeding cup fixed inside the box. The apparatus with five different kinds of openings—i.e., vertical slots, in each 2.5, 4.0 or 6.0 cm wide, a horizontal slot of 4.0 cm in width and an open space without a slot—were evaluated for an accurate measurement of undisturbed food intake. Out of these, the feeding box with a vertical slot of 4.0 cm in width, approximately 0.5–1.0 cm wider on each lateral side than the maximal transverse cranial diameter of rats, was found to be most practical; natural growth function of the body weight was not disturbed and dry food was neither scattered nor mixed up with urine and feces. The device should prove particularly useful in the measurement of dry food intake in small animals.

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.

Changes of brain serotonin and muricide behavior following chronic administration of theophylline in rats.

Temporal modification of amygdaloid serotonin (5HT) content and the resultant muricide behavior, compared to isolated and olfactory bulbectomized rats, were studied after chronic theophylline administration. Theophylline raised amygdaloid 5HT after Day 28 and amygdaloid 5-hydroxyindoleacetic acid (5HIAA), its deaminated metabolite, after Day 7. Theophylline applied for 29 days elevated 5HT and 5HIAA in the amygdala, the diencephalon and the brain stem, but not in the cortex. Effects of theophylline were reduced latency and maintained tendency to kill, even after overnight muricide test. The 5HT content of the amygdala decreased in bulbectomized rats. Discrepancy between brain 5HT changes and aggressive behavior were discussed.

Feeding patterns of theophyllinized rats and effects of dextrose on their food intake

Abstract Chronically theophylline administered rats did not show normal increase in food intake during dark periods, while the total amount of intake per 24 hr was not affected. These ingestive results were consistent with changes in arterial-venous blood glucose differences: i.e., those in the control group were markedly dependent on a light-dark feeding cycle, but not those in the theophylline group. Food containing relatively high concentrations of dextrose was found to facilitate food consumption of theophyllinized rats, an effect opposite to that on the controls. These observed changes in the feeding behavior of theophyllinized rats may reflect impaired feeding motivation and circadian desynchronization of feeding.