Hironobu Machidori

Zucker obese rats: defect in brain histamine control of feeding

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/-). Infusion of a histamine H1-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, and H3-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H1-receptor in rats.

Effect of intravenous administration of apolipoprotein A-IV on patterns of feeding, drinking and ambulatory activity of rats

To characterize the anorectic effect of apolipoprotein A-IV (apo A-IV), we examined the effect of apo A-IV on the patterns of feeding, drinking and ambulation of rats fed ad libitum. A single dose of 200, 135 or 60 micrograms was infused intravenously through a chronically indwelling right atrial catheter just before the dark period. Apo A-IV suppressed food intake by decreasing meal size, but did not affect the interval between meals, the speed of eating, or the latency to eat the first meal after infusion. The anorectic effect of apo A-IV was dose-dependent and was effective for about 3 h after the infusion. The anorectic effect of apo A-IV is specific because inactivation of apo A-IV abolishes its anorectic effect. The anorectic effect of apo A-IV is not shared by apo A-I. Apo A-IV had no effect on drinking behavior or ambulatory activity. The results seem to indicate that apo A-IV specifically decreases the meal size, which supports our hypothesis that apo A-IV may act as a physiological signal for satiation after the ingestion of a lipid meal.

Attenuation of anorexia induced by heat or surgery during sustained administration of ginsenoside Rg1 into rat third ventricle

Effects of ginsenoside Rg1 (Rg1), a major component of panax ginseng, on modulation of ingestive behavior were investigated. No direct effect was observed on food intake after 10 μl infusion of 1.0, 2.0, 4.0 or 8.0 mM Rg1 into the rat third ventricle for 10 min. Continuous osmotic infusion of 4.0 mM Rg1 at a rate of 0.966 μl/h into the third ventricle prevented feeding suppression caused by surgical procedure to implant an osmotic minipump. Continuous infusion of Rg1 attenuated anorexia, increased water intake, and decreased ambulation, that were produced by elevation of environmental temperature from 21° C to 30° C. Consequently, rats maintained body weight and rectal temperature unchanged. The results indicate that sustained central administration of Rg1 may relieve anorexia caused by implantation surgery or by a heated environment.

2,5-Anhydro-D-mannitol : its unique central action on food intake and blood glucose in rats

Peripheral administration of D-fructose has been reported to decrease food intake, and its 2-deoxy analogue, 2,5-anhydro-D-mannitol (2,5-AM), increased food intake and decreased blood glucose in rats. In the present study, 2,5-AM was selected for comparison with well-known 2-deoxy analogues of glucose. Infusion of 2,5-AM into the rat third cerebroventricle at 11.00 h induced feeding dose dependently (Y = 0.63 logX-1.20, r = 0.95, P less than 0.05). Rats treated with 2,5-AM at a maximal effective dose of 24 mumol/rat ate meals most persistently (P less than 0.05). No periprandial drinking was observed. Ambulatory activity increased concomitantly with feeding, but did not exceed the activity normally associated with a meal. Infusion of 24 mumol 2,5-AM into the third cerebroventricle induced no substantial change in plasma glucose or insulin in any 60-min experimental period. Unilateral microinfusion of 1.2 mumol 2,5-AM induced feeding in all 6 rats (P less than 0.01) when a cannula tip was located in the ventromedial hypothalamic nucleus (VMH), but not in the lateral hypothalamic area (LHA). These findings indicate that feeding elicitation may be due to disinhibition by 2,5-AM through the VMH. This is quite unique compared to the action mechanisms of hexose, pentose and their analogues, except 2,5-AM.

Acceleration of tail pinch-induced feeding in rats by analgesic effect of neurotropin

Mechanisms of tail pinch-induced feeding and effects of neurotropin (NSP), an extract from the inflamed skin of rabbit inoculated with vaccinia virus, on behavioral responses were investigated in rats. Treatment of a 5-min tail pinch (tail pinch I) induced feeding response. An intensified 15-min tail pinch (tail pinch II) provoked emotional reactions besides feeding behavior. The rate of food intake (food intake/tail pinch duration) during tail pinch II was less than that at tail pinch I. Intraperitoneal administration of NSP (100 mg/kg/day) by itself produced no remarkable change in feeding or emotional behavior. However, NSP-treated rats increased eating size and prolonged eating duration during tail pinch I. Pretreatment of NSP increased feeding behavior more potently at tail pinch II than at tail pinch I and decreased the incidence of emotional reactions at tail pinch II. The results suggest that NSP, by its analgesic action, may modulate behavioral responses during tail pinch treatment through selective blockade of the nociceptive and feeding-inhibitory information, but not through the nonnociceptive and feeding-excitatory signals.

Synergistic Effect of Meal-Scheduling Therapy and Repeated 2-Days-a-Week Administration of a Very-Low-Calorie Liquid Diet on Weight Reduction Moderately Obese Outpatients.

グラフ化体重日記等による食事確立療法に, 超低エネルギー液性食を併用し, 減量効果を検討した。対象は外来で食事確立療法施行中の中等度肥満患者13名 (すべて女性。BMI=30.1±1.3) で, 減量効果が緩徐化, ないしは停滞した者とした。超低エネルギー液性食 (オプティファースト-70®) 5包/日 (420kcal) を連続2日間毎週投与し, 4週間継続した。1日当り無カロリーの水分1, 500ml以上を摂取させた。グラフ化体重日記記載は期間中を通して継続させた。治療前後, および治療終了後, 1, 3カ月の体重を比較検討した。13名の対象中, 12名を投与終了3カ月後まで追跡した。併用療法が完了した4週目の減量幅は4.0±0.4kgであり, 有意な体重減少が得られた (p<0.01)。Body mass index (BMI) は30.4±1.4から28.7±1.5に改善した (p<0.01)。投与終了3カ月後の減量幅は4.8±1.0kg, BMIは28.6±1.5で, 減量値は維持されていた。投与終了12カ月後まで追跡できた7名でも, 減量幅は4.7±1.8 (p<0.05) であった。投与2日目に空腹感を訴えた以外は, 自, 他覚的に異常を認めなかった。食事確立療法を基盤に, 導入時期や治療効果の強度を考慮して投与すれば, 外来でも超低エネルギー液性食週2日反復投与で十分な減量効果が得られ, しかも減量維持も可能なことが判明した。