A selective orexin-1 receptor antagonist reduces food consumption in male and female rats

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over 24 h. In male rats, a single dose of SB-334867-A (30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol, i.c.v.) and feeding stimulated by an overnight fast for 4 h. When given at the start of the dark phase, food consumption was reduced in both male and female rats over 24 h. Daily injections at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orexin-A induced food intake with a selective orexin-1 receptor antagonist. Furthermore, the suppression of nocturnal feeding and food intake stimulated by an overnight fast supports other evidence that orexin-A is involved in the regulation of natural feeding and suggests that orexin-1 receptor antagonists could be useful in the treatment of obesity.     

Orexins对小鼠摄食和能量代谢的影响

目的:探讨Orexins对小鼠摄食和能量代谢的影响。方法:将小鼠分为摄食组和代谢组,摄食组通过中枢置管,注射不同剂量(1、3、10 nmol)的orexin-A和orexin-B,观察它们对小鼠摄食以及肝柠檬酸合酶活性的影响。代谢组将小鼠置于代谢笼内,通过中枢注射orexin-A,观察小鼠在光照条件、黑暗条件、禁食条件下呼吸商和代谢率的变化。结果:与对照组相比,1 nmol和10 nmol orexin-A在注射后4小时内可显著刺激小鼠进食(P0.05),而3 nmol orexin-A对摄食量的影响并不明显,但能显著促进柠檬酸合酶活性。任何剂量的orexin-B对小鼠摄食都没有显示出刺激作用(P0.05)。在光照条件下,orexin-A可显著降低呼吸商(RQ),代谢率显著升高(P0.05);而在黑暗条件下,orexin-A对RQ没有任何影响,但代谢率显著升高(P0.05);但是给禁食小鼠中注射orexin-A可诱导RQ的短暂升高,代谢率显著升高(P0.05)。结论:Orexins对小鼠摄食与能量代谢可能有一定的调控作用。     

Orexin-A does not stimulate food intake in old rats

Aging is associated with a progressive decrease in appetite and food intake. Both A and B orexins, expressed in specific neurons of the lateral hypothalamic area, have been implicated in the regulation of sleep and feeding. In this study, the stimulatory effect of intracerebroventricular administration of the orexins on food intake was compared between young (4-mo-old) and old (25- to 27-mo-old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses (0-30 nmol) of orexins were injected into the left lateral ventricle without anesthesia. Food and water consumptions were measured at 1, 2, and 4 h after injection. The protein levels of orexin receptors, a specific receptor for orexin-A (OX1R) and a receptor for both orexin-A and -B (OX2R), in the hypothalamus were determined by Western blot analysis and compared between young and old rats. Intracerebroventricular administration of orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. The protein level of OX1R in the hypothalamus was significantly lower in old rats than in young rats, although the protein level of OX2R was comparable between groups. Results of the present study indicate that the function of the orexin system is diminished in old rats. The decrease in the OX1R protein level in the hypothalamus could be responsible for orexin-A's lack of stimulation of food intake in old rats.     

Orexin-induced feeding requires NMDA receptor activation in the perifornical region of the lateral hypothalamus

Food intake is stimulated following administration of orexin-A into the perifornical region of the lateral hypothalamus (LH/PFA). Orexin neurons originating in the LH/PFA interact with a number of hypothalamic systems known to influence food intake, including glutamatergic neurons. Glutamatergic systems in the LH/PFA were demonstrated to initiate feeding through N-methyl-d-aspartic acid (NMDA) receptors. Male Sprague-Dawley rats fitted with brain guide cannulas to the LH/PFA were used in two experiments. In the first experiment, a combination microdialysis/microinjection probe was used to deliver artificial cerebrospinal fluid (aCSF) or 500 pmol of orexin-A into the LH/PFA. Orexin-A increased interstitial glutamate to 143 +/- 12% of baseline (P < 0.05), which remained elevated over the 120-min collection period. In the second experiment, the NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 10 nmol) was administered before orexin-A. The orexin-induced increase in food intake (from 1.1 +/- 0.4 to 3.2 +/- 0.5 g, P < 0.05) during the first hour was absent in rats receiving d-AP5 + orexin-A (1.2 +/- 0.5 g). There was no effect of d-AP5 alone on food intake. These data support glutamatergic systems in the LH/PFA mediating the feeding response to orexin-A through NMDA receptors.     

下丘脑室旁核orexin-A对大鼠摄食和胃动力影响及调控机制

目的:探讨下丘脑室旁核orexin-A对大鼠摄食和胃动力影响及调控机制。方法:采用免疫组化观察下丘脑室旁核(paraventricular nucleus,PVN)orexin受体表达情况;PVN注射orexin-A观察大鼠摄食、胃运动、胃酸分泌和胃排空的改变。结果:免疫组化实验显示大鼠PVN中存在orexin受体免疫阳性细胞。PVN注射orexin-A后,大鼠前三小时摄食增加,6 h和24 h摄食无显著改变。PVN微量注射orexin-A后,大鼠胃运动幅度和频率增加、胃排空增快并且胃酸分泌增多。[D-Lys-3]-GHRP-6可部分阻断orexin-A对摄食、胃运动、胃排空和胃酸分泌的促进作用,SB334867可完全阻断orexin-A对胃运动、胃排空和胃酸分泌的促进作用。结论:下丘脑室旁核orexin-A可能通过生长激素促泌素GHSR受体信号通路调控大鼠摄食及胃功能。     

Orexin-A受体介导的生长抑素激动剂ODT8-SST对大鼠摄食和饮水的影响

目的：探讨orexin-A（OXA）受体介导的生长抑素激动剂ODT8-SST 对大鼠摄食和饮水的调节作用相关作用机制。方法：在光 照周期内,大鼠40 只随机分8 组,侧脑室（icv）分别注射不同剂量ODT8-SST 或生理盐水（NS）;大鼠56 只随机分8 组分别侧脑 室注射不同剂量OXA 受体（OX1R）拮抗剂SB-334867 或NS;2小时后测量大鼠摄食量和饮水量。结果：与NS组相比,实验组大 鼠侧脑室注射ODT8-SST（1 ug/rat）,2 小时后摄食量和饮水量均显著增加（P<0.05）。大鼠侧脑室注射SB-334867（16 ug/rat）完全 抑制了由侧脑室注射ODT8-SST 后引起的摄食量和饮水量的增加;与此相反,大鼠给予SST2 拮抗剂S-406-028 预处理之后,可阻 止侧脑室注射ODT8-SST 引发的促进食欲作用,但不会影响侧脑室注射OXA（10.7 ug/rat）诱导的摄食量和饮水量的增加。结论： 侧脑室注射ODT8-SST 可促进摄食和饮水,该过程可能由OX1R所介导;orexin-A 促进摄食作用不依赖大脑SST2 通路的激活。     

Effect of intraperitoneal CCK-8 on food intake and brain orexin-A after 48 h of fasting in the rat

We investigated the interactions of the peripheral satiety peptide cholecystokinin and the brain orexin-A system in the control of food intake. The effect of an intraperitoneal (i.p.) injection of sulfated cholecystokinin octapeptide (in this article called CCK) (5 microg/kg, 4.4 nmol/kg) or of phosphate-buffered saline (PBS, vehicle control) on 48 h fasting-induced feeding and on orexin-A peptide content was analyzed in diverse brain regions innervated by orexin neurons and involved in the control of food intake. Administration of CCK after a 48 h fast reduced fasting-induced hyperphagia (P<0.05). I.p. CCK increased the orexin-A content in the posterior brainstem of 48 h fasted rats by 35% (P<0.05). Fed animals receiving CCK had 48% higher orexin-A levels in the posterior brainstem than fasted rats (P<0.05). In the lateral hypothalamus, fasting decreased orexin-A levels by 50% as compared to fed rats (P<0.05). In the septal nuclei, the combination of fasting and CCK administration reduced orexin-A contents compared to fed PBS and CCK animals by 13% and 17%, respectively (P<0.05). These results suggest a convergence of pathways activated by peripheral CCK and by fasting on the level of orexin-A released in the posterior brainstem and provide evidence for a novel interaction between peripheral satiety signaling and a brain orexigen in the control of food intake.     

Evidence for the role of hindbrain orexin-1 receptors in the control of meal size

Hypothalamic orexin neurons project to the hindbrain, and 4th-ventricle intracerebroventricular (4th-icv) injection of orexin-A treatment increases food intake. We assessed the effects of hindbrain orexin-A and the orexin-1-receptor antagonist SB334867 on meal pattern in rats consuming standard chow. When injected 4th-icv shortly before dark onset, lower doses of orexin-A increased food intake over a 2-h period by increasing the size of the first meal relative to vehicle, whereas the highest dose increased food intake by causing the second meal to be taken sooner. Conversely, hindbrain SB334867 reduced food intake by decreasing the size of the first meal of the dark phase. We also examined the effects of 4th-icv orexin-A and SB334867 on locomotor activity. Only the highest dose of orexin-A increased activity, and SB334867 had no effect. In addition, hindbrain SB334867 induced c-Fos in the nucleus of the solitary tract. These data support the suggestion that endogenous hindbrain orexin-A acts to limit satiation. Both orexin-A and the pancreatic satiation hormone amylin require an intact area postrema to affect food intake, so we asked whether 4th-icv orexin-A impairs the satiating effect of peripheral amylin treatment. Amylin reduced the size of the first meal of the dark cycle when rats were pretreated with 4th-icv saline, yet amylin was ineffective after 4th-icv orexin-A pretreatment. Using double-label immunohistochemistry, we determined that some orexin-A fibers in the area postrema are located in proximity to amylin-responsive neurons. Therefore, hindbrain orexin-A may increase food intake, in part, by reducing the ability of rats to respond to amylin during a meal.     

Food-induced expression of orexin receptors in rat duodenal mucosa regulates the bicarbonate secretory response to orexin-A

Presence of appetite-regulating peptides orexin-A and orexin-B in mucosal endocrine cells suggests a role in physiological control of the intestine. Our aim was to characterize orexin-induced stimulation of duodenal bicarbonate secretion and modulation of secretory responses and mucosal orexin receptors by overnight food deprivation. Lewis x Dark Agouti rats were anesthetized and proximal duodenum cannulated in situ. Mucosal bicarbonate secretion (pH stat) and mean arterial blood pressure were continuously recorded. Orexin-A was administered intra-arterially close to the duodenum, intraluminally, or into the brain ventricles. Total RNA was extracted from mucosal specimens, reverse transcribed to cDNA and expression of orexin receptors 1 and 2 (OX1 and OX2) measured by quantitative real-time PCR. OX1 protein was measured by Western blot. Intra-arterial orexin-A (60-600 nmol.h(-1).kg(-1)) increased (P < 0.01) the duodenal secretion in fed but not in fasted animals. The OX1 receptor antagonist SB-334867, which was also found to have a partial agonist action, abolished the orexin-induced secretory response but did not affect secretion induced by the muscarinic agonist bethanechol. Atropine, in contrast, inhibited bethanechol but not orexin-induced secretion. Orexin-A infused into the brain ventricles (2-20 nmol.kg(-1).h(-1)) or added to luminal perfusate (1.0-100 nM) did not affect secretion, indicating that orexin-A acts peripherally and at basolateral receptors. Overnight fasting decreased mucosal OX1 and OX2 mRNA expression (P < 0.01) as well as OX1 protein expression (P < 0.05). We conclude that stimulation of secretion by orexin-A may involve both receptor types and is independent of cholinergic pathways. Intestinal OX receptors and secretory responses are markedly related to food intake.     

Obestatin对血浆ghrelin和nesfatin-1水平及胃排空的影响

目的:探讨侧脑室注射obestatin对大鼠血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平的影响以及对胃排空的调控。方法:侧脑室注射obestatin,采用酶免疫测定(EIA)法检测血浆酰基化ghrelin、去酰基化ghrelin、nesfatin-1水平以及胃排空率的变化。结果:侧脑室分别注射0.1、0.3或1.0 nmol obestatin,大鼠血浆酰基化ghrelin、去酰基化ghrelin以及nesfatin-1水平无显著改变(P0.05),且酰基化ghrelin与去酰基化ghrelin比率无显著改变(P0.05);侧脑室注射obestatin,大鼠摄食量无显著改变,但胃排空率明显增加(P0.05);胃排空率明显延迟(P0.05)。与侧脑室注射1.0 nmol Obestatin组相比,注射1.0 nmol Obestatin+CRF,大鼠摄食量无显著改变,胃排空率明显延迟(P0.05)。各组摄食量及进入十二指肠内食物量无明显差异(P0.05)。结论:中枢obestatin促进大鼠的胃排空,可能与h/r CRF通路有关。     

禁食不同时段下丘脑穹窿周区orexin-A的表达

目的探讨禁食不同时段大鼠下丘脑穹窿周区orexin—A的表达及是否与摄食有关。方法观察禁食前后大鼠体重变化,采用免疫组织化学染色法观察禁食不同时段下丘脑穹窿周区orexin-A的表达变化,灰度值测量观察各组orexin—A的染色强度。结果大鼠体重随禁食时间的延长而逐渐降低,各组大鼠禁食前后体重变化有统计学差异（P〈O．01）;Orexin-A主要分布于下丘脑穹窿周区,禁食组orexin—A阳性神经元计数明显多于对照组（P〈O．05）,但不同禁食组间orexin-A阳性神经元计数比较没有统计学差异（P〉O．05）;禁食48h组染色强度最深,与对照组和禁食24h、72h组有明显统计学差异（P〈0．05）。结论禁食可以促进orexin-A的表达,禁食48h应该是一种理想的促进orexin-A活化的刺激方式,orexin-A系统可能参与摄食及能量代谢的调节。     

伏隔核微注射orexin-A 对大鼠摄食和活动的影响

目的:探讨伏隔核微注射orexin-A后,大鼠摄食和活动的变化。方法:采用SD大鼠(250-280g),用脑立体定位仪在伏隔核植入微量注射管。大鼠随机分组,分别微注射乳酸格林液(Ringer’s),orexin-A 100pmol和500pmol。观察微注射后大鼠0-1h,1-2h,2-4h摄食和0-30min,30-60min,60-90min,90-120min活动性变化。结果:Orexin-A微注射后,大鼠0-1h,1-2h摄食量增加;30-60min,60-90min,90-120min的活动性显著增加(P<0.05 vs对照组)。结论:伏隔核是orexin-A刺激大鼠增加摄食量,提高其活动性的作用点。     

Inhibition of food intake by central injection of anti-orexin antibody in fasted rats

It has been shown that intracerebroventricular injection of synthetic orexins stimulated food intake in rats. This pharmacological evidence suggests that orexins may have a role for the central regulation of feeding. In the present study, we investigated the hypothesis of whether endogenous orexins indeed play a vital role in feeding behavior. An anti-orexin polyclonal antibody was used throughout the study. First, we examined the specificity of the antibody to orexin by Western blot analysis and immunohistochemistry. Next, the effects of central injection of the orexin antibody on food intake in 24-h-fasted rats were evaluated. Western blot analysis revealed that the orexin antibody detected synthetic orexin-A. Immunohistochemical study showed that orexin-positive neurons were identified only in the lateral hypothalamic area, in agreement with previous reports. Neither control antibody nor the orexin antibody preabsorbed with excess amount of orexin-A detected neurons, indicating that the orexin antibody is specific. Intracisternal but not intraperitoneal injection of the orexin antibody dose-dependently suppressed feeding. All these results suggest that immunoneutralization of endogenous orexins in the brain reduced food intake. In other words, we suggest that endogenous brain orexin may have a physiologically relevant action on feeding behavior.     

Effects of orexin-A on memory processing

Orexin-A is an endogenous peptide with receptors present throughout the brain. Here, we examined the effect of post-training administration of orexin-A on retention in active and passive avoidance. Orexin-A administered by intracerebroventricular (i.c.v.) injection to CD-1 mice post-training improved retention in both T-maze footshock avoidance and one trial step-down passive avoidance. SAMP8 mice have age-related deficits in learning and memory, which correlate with an increase in brain levels of beta amyloid (Abeta) and an impaired response to memory-enhancing compounds. Orexin-A at 3nmol improved retention in young and old SAMP8 mice. These findings show that orexin-A can improve memory even with overproduction of Abeta.     

Effect of enterostatin given intravenously and intracerebroventricularly on high-fat feeding in rats.

The effect of enterostatin, the amino-terminal pentapeptide of pancreatic procolipase, on high-fat food intake has been investigated after intracerebroventricular as well as after intravenous injection. After an overnight fast enterostatin given i.c.v. at doses of 167 pmol and 333 pmol produced a significant and dose-dependent reduction in high-fat food intake, while a higher dose of 667 pmol had no effect. Following intravenous injection of enterostatin the intake of high-fat food was suppressed at doses of 8.3 nmol and 16.7 nmol, while no effect was observed at higher doses. The inhibition of feeding started 3 h after the initiation of feeding and persisted to the end of the test period (6 h). Enterostatin at a dose of 16.7 nmol gave no sign of aversion in an aversion test comparing the effect of enterostatin, lithium chloride and saline on liquid intake. The data suggest that enterostatin may exert its satiety effect on high-fat feeding by being absorbed into the bloodstream.     

Carbon monoxide is the heme oxygenase product with a pyretic action: evidence for a cGMP signaling pathway

We have recently reported that the central heme oxygenase (HO) pathway has an important role in the genesis of lipopolysaccharide fever. However, the HO product involved, i.e., biliverdine, free iron, or carbon monoxide (CO), has not yet been identified with certainty. Therefore, in the present study, we tested the thermoregulatory effects of all HO products. Body core temperature (T(c)) and gross activity of awake, freely moving rats was measured by biotelemetry. Intracerebroventricular administration of heme-lysinate (152 nmol), which induces the HO pathway, evoked a marked increase in T(c), a response that was attenuated by intracerebroventricular pretreatment with the HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (200 nmol), indicating that an HO product has a pyretic action in the central nervous system (CNS) of rats. Besides, heme-lysinate also increased gross activity, but no correlation was found between this effect and the increase in T(c). Moreover, intracerebroventricular biliverdine or iron salts at 152 nmol, a dose at which heme-lysinate was effective in increasing T(c), produced no change in T(c). Accordingly, intracerebroventricular treatment with the iron chelator deferoxamine elicited no change in basal T(c) and did not affect heme-induced pyresis. However, heme-induced pyresis was completely prevented by the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. Because biliverdine and iron had no thermoregulatory effects and CO produces most of its actions via sGC, these data strongly imply that CO is the only HO product with a pyretic action in the CNS.     

Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats

Although intracerebroventricular (i.c.v.) administration of orexin-A has been reported to stimulate food intake and/or feeding behaviour in rats, mice and goldfish, little attention has thus far been paid to its effects on normal patterns of feeding. In the present study, a continuous monitoring technique was used to characterise the effects of this novel neuropeptide on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Particular attention was devoted to the behavioural satiety sequence, in which feeding is followed by grooming and resting. Although results confirmed the hyperphagic effects of orexin-A (3.33-30.0 microg i.c. v.), gross behavioural analysis failed to reveal any reliable effects of peptide treatment on eating, drinking, sniffing, grooming, resting, locomotion or rearing. However, microstructural analysis revealed behavioural effects of orexin-A that are both dose- and time-dependent. At lower doses (3.33-10.0 microg), orexin-A primarily delayed behavioural satiety, i.e. the normal transition from eating to resting. In contrast, the 30 microg dose initially induced a sedative-like effect, significantly suppressing eating and other active behaviours for the first 15-20 min of the test period. This sedative-like effect resulted in a phase-shifting of the entire behavioural sequence with higher than control levels of eating, grooming, locomotion, rearing and sniffing observed over the second half of the test session. Present findings illustrate the advantages of microstructural behavioural analysis and suggest that the hyperphagic response to low doses of orexin-A results largely from a delay in behavioural satiety while that seen in response to high doses may occur in rebound to initial behavioural suppression. Further studies will be required to confirm the identity of the specific orexin receptors (i.e. OX(1) or OX(2)) involved in mediating the dose-dependent behavioural effects reported.     

DVC orexin-A通过调控ghrelin受体信号通路改善顺铂所致大鼠胃功能紊乱

目的:探讨迷走神经复合体(Dorsal vagal complex,DVC)内orexin-A对顺铂所致胃功能紊乱的影响及可能机制。方法:随机选取30只大鼠并将其分为3组(n=10):对照组(NS组);24 h顺铂治疗组;48 h顺铂治疗组。24 h顺铂治疗组和48 h顺铂治疗组大鼠分别在腹腔注射顺铂后24 h和48 h处死大鼠,对照组大鼠腹腔注射生理盐水(Normal saline,NS)。采用定量实时PCR检测各组大鼠下丘脑orexin-A mRNA的表达,ELISA测量大鼠脑脊液中P物质水平;DVC内微量注射orexin-A和ghrelin受体拮抗剂后,检测大鼠食物和高岭土的摄入量。结果:顺铂可显著减少大鼠下丘脑orexin-A mRNA表达,增加其脑脊液内P物质的浓度。外源性orexin-A可改善顺铂引起的厌食症和异食癖。orexin-A以上的效应可被DVC内预先注射ghrelin受体拮抗剂部分逆转。结论:orexin-A可能通过ghrelin神经肽系统改善顺铂在化疗过程中诱导的胃功能紊乱。     

第四脑室注射Orexin-A对大鼠饮食摄取条件性位置偏爱的影响

目的:探讨第四脑室注射orexin-A(OXA)对大鼠饮食摄取条件性位置偏爱的影响。方法:将30只大鼠随机分成3组,即对照组,低剂量组和高剂量组,第四脑室分别注射生理盐水(NS)、orexin-A或orexin-A受体拮抗剂SB334867,观察大鼠按压杠杆获取蔗糖的次数和最高频率的变化。再选择30只大鼠,第四脑室注射orexin-A和SB334867,观察大鼠对高脂饮食(HF)食物的摄入量。另选取30只大鼠第四脑室注射orexin-A或SB334867,将大鼠置于条件位置偏爱箱来检测大鼠对HF条件性位置偏爱的变化。结果:与对照组相比,24小时禁食大鼠,第四脑室注射orexin-A,可显著增加大鼠按压杠杆获取蔗糖的次数和最高频率(P0.05)。而SB334867可显著降低大鼠按压杠杆获取蔗糖次数以及最大频率(P0.05)。第四脑室注射orexin-A,可使大鼠HF摄入量显著增加(P0.05),第四脑室注射SB334867,不影响大鼠HF摄入量,但会抑制普通饮食的摄入(P0.05)。第四脑室注射orexin-A能增强对HF饮食位置偏爱性的表达,注射SB334867后会显著抑制大鼠对HF饮食位置偏爱性的表达(P0.05)。结论:第四脑室注射Orexin-A可影响大鼠摄食行为,增加高脂饮食的摄入量,增强对HF饮食位置偏爱性的表达。     

Injection of neuropeptide W into paraventricular nucleus of hypothalamus increases food intake

Neuropeptide W (NPW) is an endogenous ligand for G protein-coupled receptor 7 (GPR7). There are two forms of the peptide, designated as neuropeptide W-23 (NPW23) and neuropeptide W-30 (NPW30). In the current study we found that intracerebroventricular administration of NPW23 increased c-Fos immunoreactivity (IR) in a variety of brain sites, many of which are involved in the regulation of feeding. In particular, we noted that c-Fos IR levels were increased in hypocretin-expressing neurons in the perifornical region of the lateral hypothalamus (LH). We then studied whether injection of NPW23 into the paraventricular nucleus of the hypothalamus (PVN) and the LH increased food intake over a 24-h time period. Intra-PVN injection of NPW23 at doses ranging from 0.1 to 3 nmol increased feeding for up to 4 h, and doses ranging from 0.3 to 3 nmol increased feeding for up to 24 h. In contrast, only the 3-nmol dose of NPW23 increased feeding after administration into the LH. Together, these data suggest a modulatory role for NPW in the control of food intake.