Koji Fukagawa

Suppression of Food Intake by Apolipoprotein A-IV Is Mediated through the Central Nervous System in Rats

The aim of this experiment was to investigate whether the anorectic effect of apolipoprotein A-IV (apo A-IV) after lipid feeding is mediated via the central nervous system. Infusion of 0.5 micrograms of apo A-IV into the third ventricle failed to suppress food intake. Higher doses (1 micrograms or higher) of apo A-IV infused into the third ventricle inhibited food intake in a dose-dependent manner. In contrast, when apo A-I was infused into the third ventricle it had no effect on food intake. To further test the hypothesis that apo A-IV is an important factor controlling food intake, we administered goat anti-rat apo A-IV serum into the third ventricle of rats that were allowed food and water and lib. In all rats tested, this treatment resulted in enhanced food intake. In contrast, infusion of goat anti-rat apo A-IV serum failed to elicit such a response. Lastly, we determined the apo A-IV concentration in plasma and cerebrospinal fluid before and during active lipid absorption. Apo A-IV concentration in cerebrospinal fluid was about 1/20 that of plasma. Both serum and cerebrospinal fluid apo A-IV increased markedly as a result of feeding of lipid. In conclusion, we propose that apo A-IV may act centrally to control food intake.

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.

Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior

Glucagon‐like peptide‐1 (GLP‐1), corticotropin‐releasing hormone (CRH), and hypothalamic neuronal histamine suppress food intake, a target of leptin action in the brain. This study examined the interactions of GLP‐1, CRH, and histamine downstream from the leptin‐signaling pathway in regulating feeding behavior. Infusion of GLP‐1 into the third cerebral ventricle (i3vt) at a dose of 1 µg significantly decreased the initial 1 h cumulative food intake in rats as compared with phosphate‐buffered saline (PBS) controls. The GLP‐1‐induced suppression of feeding was partially attenuated by intraperitoneal pretreatment with α‐fluoromethylhistidine (FMH), a specific suicide inhibitor of histidine decarboxylase, which depletes hypothalamic neuronal histamine. Pretreatment with α‐helical CRH (10 µg/rat, i3vt), a nonselective CRH antagonist, abolished the GLP‐1‐induced suppression of feeding completely. I3vt infusion of GLP‐1 increased the CRH content and histamine turnover assessed using the pargyline‐induced accumulation of tele‐methyl histamine (t‐MH), a major metabolite of neuronal histamine, in the hypothalamus. The central infusion of CRH also induced the increase of histamine turnover and CRH receptor type 1 was localized on the cell body of histamine neuron. Pretreatment with exendin(9–39), a GLP‐1 receptor antagonist, attenuated the leptin‐induced increase in CRH content of the hypothalamus. Finally, i3vt infusion of leptin also increased histamine turnover in the hypothalamus. Pretreatment with exendin(9–39), α‐helical CRH or both antagonists attenuated the leptin‐induced responses of t‐MH levels in the hypothalamus. These results suggest that CRH or hypothalamic neuronal histamine mediates the GLP‐1‐induced suppression of feeding behavior, that CRH mediates GLP‐1 signaling to neuronal histamine and that a functional link from GLP‐1 to neuronal histamine via CRH constitutes the leptin‐signaling pathway regulating feeding behavior.

Food consistency modulates eating volume and speed through brain histamine in rat

Changes in meal parameters of rats fed with different consistency of food were examined using hard and soft pellets. Meal size and eating speed of the first meal after 1800 h increased significantly in rats fed with soft pellets compared to those fed with hard pellets. Effects of histamine depletion on meals treated with hard or soft pellets were investigated after an intraperitoneal injection of 0.11 mmol/kg alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of the histamine synthesizing decarboxylase enzyme. When rats were fed with hard pellets, FMH significantly decreased eating speed and prolonged meal duration without affecting meal size. When rats were fed with soft pellets, FMH increased meal size and duration, but not eating speed. The meal parameter of eating speed was significantly decreased and meal size and duration were increased in obese Zuckers, a hereditary histamine-depleted animal model, when compared to their lean littermates. These results indicate that proprioceptive sensation from the oral cavity may regulate meal parameters through histaminergic neurons in the brain.