Kazuma Fujimoto

Blockade of the histamine H1-receptor in the rat ventromedial hypothalamus and feeding elicitation

All H1-, but no H2-antagonists infused into the rat third cerebroventricle, induced feeding during the early light, but not during the early dark, reflecting a concentration of hypothalamic histamine. Bilateral microinfusion identified the ventromedial hypothalamus (VMH), but not the lateral hypothalamus or the paraventricular nucleus, as a main locus for the induction of feeding by an H1-antagonist. The effect was completely abolished when brain histamine was decreased by pretreatment with alpha-fluoromethylhistidine. Hypothalamic neuronal histamine suppresses food intake, at least in part, through H1-receptors in the VMH.

Hypothalamic sites of neuronal histamine action on food intake by rats.

To identify sites of histaminergic modulation of food intake, histamine H1-receptor antagonist was microinfused into the rat hypothalamus, the ventromedial hypothalamus (VMH), the lateral hypothalamus (LHA), the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), or the preoptic anterior hypothalamus (POAH), during the early light period. Feeding, but not drinking, was elicited in 100% of the rats (P less than 0.01) that were bilaterally microinfused with 26 nmol chlorpheniramine into the VMH. Unilateral infusion into the VMH did not affect food intake at doses of 26 or 52 nmol. Feeding was also induced by bilateral microinfusion into the PVN, but only the 52 nmol dose was effective. Bilateral infusions into the LHA, the DMH or the POAH did not affect ingestive behavior. Feeding induced by an H1-antagonist was completely abolished in all 7 rats tested when endogenous neuronal histamine was decreased by pretreatment with alpha-fluoromethylhistidine (100 mg/kg). The findings suggest that H1-receptors in the VMH and the PVN, but not in the LHA, the DMH or the POAH, may be involved in histaminergic suppression of food intake.

Hypothalamic neuronal histamine modulates ad libitum feeding by rats

Manipulating histamine endogenously, its effects on brain functions were assessed in rats. alpha-Fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, elicited feeding (P less than 0.01) after intra-third cerebroventricular infusion at the early light phase when hypothalamic histamine was normally highest. No periprandial drinking was observed. The effect of FMH was attenuated, and thioperamide, an antagonist of auto-inhibitory effects on both histamine synthesis and release at presynaptic H3-receptor, conversely suppressed food intake (P less than 0.05), when these probes were carried out during the minimum histamine level early in the dark period. Bilateral microinfusion of FMH into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) selectively induced feeding, but the infusion into the remaining sites of the hypothalamus had no effect. These data show that neuronal histamine plays a physiological role in feeding suppression through the VMH and the PVN in the rat.

Feeding induced by blockade of histamine H1-receptor in rat brain

Histamine antagonists were infused into the third ventricle of the cerebrum in rats. All the H1-, but none of the H2-antagonists tested, induced initial feeding during the early portion of the light phase when histamine level was highest. No periprandial drinking was observed. Ambulation increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early portion of the dark phase, or was decreased by α-fluoromethylhistidine. Hypothalamic neuronal histamine may suppress food intake through H1-receptors, and diurnal fluctuations of food intake may mirror neuronal histamine levels.

D-glucose suppression of eating after intra-third ventricle infusion in rat

To clarify the hypophagic action of D-glucose, meal size, postprandial intermeal interval and eating rate were analyzed after infusion of glucose into the third cerebroventricle. The effects of glucose structure modification on feeding modulation were examined by comparing the effects of glucose to those of its epimers, D-mannose, D-allose and D-galactose. Glucose, infused in doses of 6 to 24 mumol, dose relatedly reduced meal size, but did not change other meal parameters. The minimum dose of glucose to induce feeding suppression was between three and 6 mumol. The epimers, at doses of 24 mumol, did not affect food intake or body weight. Drinking patterns and ambulatory activity were not changed by glucose infusion. These findings were consistent with neuronal activity observed in the ventromedial hypothalamic nucleus.

Charting of Daily Weight Pattern Reinforces Maintenance of Weight Reduction in Moderately Obese Patients

To maintain reduced body weight by behavioral therapy in moderately obese patients, body weight was measured four times daily and charted in a weekly graph. Seventy-two female patients with simple obesity were divided into two groups: 55 patients with appliance of charting of weight pattern (group-I), and 17 patients without the charting (group-II). The percentage of patients followed for 2 years was different between group-I (87%) and group-II (65%) during 2 years after completion of weight reduction therapy interviews (p less than 0.05). Forty-eight of group-I patients succeeded in decreasing their weight by 15.2 +/- 1.5 (mean +/- SEM) kg during the 6.5 +/- 0.8 months of the therapy interviews. They were followed up for 3.8 years with no rebound weight gain. Eleven patients in group-II also succeeded in decreasing their weight by 16.8 +/- 1.9 kg during 7.8 +/- 1.3 months but their body weight rebounded by 9.0 kg during the 2-year followup period. Twelve of 15 male patients with weight charting maintained reduced weight during 4.3 years. It was easier and more effective for obese patients to maintain weight graphs for the longer period than to record no weight graphs. Obese patients could themselves monitor irregular weight patterns produced by overeating and correct the irregularities in food intake and daily lifestyles. This seems to explain why the illustration of daily fluctuations of weight measurements was useful for long-term maintenance of weight reduction.

Modulation of neuronal histamine in control of food intake

Neuronal histamine affects physiological functions of the hypothalamus. To investigate involvement of histamine receptors in feeding, histamine antagonists were infused into the rat third cerebroventricle. All H1- but no H2-antagonists tested, induced transient feeding during the early light when concentration of hypothalamic histamine was highest. No periprandial drinking was observed. Ambulation concomitantly increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early dark or was decreased by alpha-fluoromethylhistidine (alpha-FMH). Bilateral microinjection indicated that the ventromedial hypothalamus, but not the lateral hypothalamus or the paraventricular nucleus, was a main locus for the induction of feeding by an H1-antagonist. The effect was completely abolished when brain histamine was decreased by pretreatment with alpha-FMH. Hypothalamic neuronal histamine suppresses food intake, at least in part, through H1-receptors in the VMH, and diurnal fluctuations of food intake may mirror neuronal histamine level.

Hypothalamic histamine modulates adaptive behavior of rats at high environmental temperature

Histamine content in the rat hypothalamus was lower at 4°C and higher at 31°C compared to that at 21°C. Pretreatment with α-fluoromethylhistidine, a ‘suicide’ inhibitor of histidine decarboxylase, attenuated both the increased level of hypothalamic histamine and rat adaptive behavior at 31°C. Increase of histamine content in the hypothalamus appears to be an important factor contributing to rat adaptive behavior to high environmental temperature.

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.

Histaminergic control of energy balance in rats

Manipulating neuronal histamine in the hypothalamus, its effects on brain functions were assessed in nonobese normal rats and Zucker rats. Alpha-fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, induced feeding dose-dependently after 2.24 mumol infusion at 1100 h, when hypothalamic histamine was normally high. This dose of FMH selectively decreased hypothalamic histamine, but not other neurotransmitters. Thioperamide, an antagonist of autoinhibitory H3-receptors, decreased food intake after infusion at 1940 h, when hypothalamic histamine was normally low. Bilateral microinfusion of 224 nmol FMH or 26 nmol chlorpheniramine, an H1-antagonist, into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN), elicited feeding. However, Zucker obese rats showed no significant responses to chlorpheniramine, thioperamide or histamine. Concentration of their hypothalamic histamine was excessively lower than that of the nonobese. Contents of hypothalamic histamine were lowered at 4 degrees C and raised at 31 degrees C. FMH attenuated increase in histamine, and then disrupted adaptive behavior. These findings indicate that neuronal histamine may convey the suppressive signal of food intake through H1-receptors in the VMH and/or the PVN, and play critical roles in homeostatic control of adaptive behavior.