Reduction of food intake and body weight by chronic intraventricular insulin infusion

This study examined the effect of chronic infusions of insulin in one of three doses (5, 7.5 or 10 mU/day) into the third ventricle, on food and water intake and body weight in the rat. Solutions were infused via osmotic minipumps at a rate of 1 microliter/hour for seven days. The two highest doses of insulin produced a dose-related suppression of food intake and weight loss, which was greater than the effect produced by 5 mU/day or a control infusion of Ringers solution. The effect of 5 mU/day on food and water intake and body weight was similar to the effect of the control infusion. All groups treated with insulin decreased food intake during the day and night, although only differences in nighttime food intake were statistically significant. Ten mU/day also produced a significantly greater reduction in water intake than each of the other solutions. Weight loss in the animals infused with insulin could not be explained by a decrease in caloric intake alone. Food intake returned to normal in all groups by the end of a seven day post-infusion period, with recovery being slowest among the animals receiving the highest doses of insulin. All animals recovered body weight at approximately the same rate. These results provide further evidence for the view that brain insulin plays a role in the regulation of food intake and body weight.     

第二代抗精神病药对大鼠血糖、胰岛素和C肽分泌的影响

目的 了解第二代抗精神病药(氯氨平、奥氮平、喹硫平、阿立哌唑)对大鼠体重、空腹血糖、胰岛素和C肽分泌的影响.方法 25只雌性SD(Sprague Dawley,SD)大鼠随机均分成5组.分别给予氯氮平20 mg/(kg·d)、奥氮平5 mg/(kg·d)、喹硫平20 mg/(kg·d)、阿立哌唑5mg/(kg·d)和生理盐水灌胃,共28 d.在第1、7、14、28天分别剪尾采血,测体重及空腹血糖,于第28天测定空腹血浆胰岛素和C肽水平.结果 适应性喂养1周后,5组大鼠的空腹血糖和体重水平差异无统计学意义(P＞0.05).持续灌胃第14及28天,氯氮平、奥氮平和喹硫平组空腹血糖高于空白时照组(P＜0.05);持续灌胃28 d,氯氮平、奥氮平组的体重高于空白对照组(P＜0.05);与未加处理因素前(第1天)相比,氯氮平、奥氮平和喹硫平组体重和空腹血糖随时间的延长而增加(P＜0.05),而阿立哌哇组的变化无统计学意义(P＞0.05).持续灌胃第28天,氯氮平、奥氮平和喹硫平组空腹血浆胰岛素和C肽水平高于空白对照组(P＜0.05);而阿立哌唑组变化不明显(P＞0.05).结论 氯氮平、奥氮平、喹硫平可引起大鼠胰岛素抵抗和血糖代谢异常.     

The effects of semi- and HPLC-purified human satietin and alpha-1-glycoprotein on ingestion and body weight

Satietin is thought to be an endogenous glycoprotein that can suppress food intake (FI) and body weight (b.wt.). In Experiment 1, rats were ICV infused with either a-CSF or with 50 micrograms/rat of human satietin. FI was suppressed (p less than 0.05) for 2 days after infusion, whereas b.wt. was attenuated (p less than 0.05) for 14 days. In Experiment 2, the previously thought homogenous human satietin was further purified by HPLC and this yielded two peaks (A and B). Rats were ICV infused with either a-CSF or 50 micrograms/rat of Peak A, Peak B or the semipurified parent human satietin (sph-SAT) from which the peaks were derived. All three treatments suppressed (p less than 0.05) FI on day 1 after infusion and on day 2 in the groups that received Peak A and sph-SAT. Body weight was attenuated (p less than 0.01) in all the experimental groups on day 1 and for 2 and 10 days, respectively, in the Peak A and sph-SAT-treated groups. Immunostaining revealed Peak A contained both albumin and alpha-1-glycoprotein (A1G), whereas Peak B contained neither. In the last experiment rats were ICV infused with either a-CSF or 50 micrograms/rat of A1G or A1G that was put through the sph-SAT extraction procedure. FI was suppressed (p less than 0.01) and b.wt. attenuated in both experimental groups only on the first day postinfusion. These data suggest that some, but possibly not all, of the previously found biological activity attributed to sph-SAT might be due to contaminants of the preparation.     

Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet

(1) Offering preferred foods in addition to laboratory chow led immediately to a marked increase in both mean meal size (MMS) and meal frequency (MF). (2) As body weight increased over a 5 months period, MF declined to a low level but MMS remained high. (3) Within a majority of meals there was substantial consumption of only one food item. Nonetheless, when “mixed” meals were eaten these were usually larger than “exclusive” meals. (4) With more than one preferred food available there was a significant tendency to alternate consumption of food types from one meal to the next. This disappeared at inter-meal intervals longer than 90 minutes. (5) With one preferred food available, only MMS (and not MF) was increased and the degree of hyperphagia and obesity were reduced. The findings suggest the following conclusions: Both palatability (preference value for a particular food) and variety (availability of different types of food) have incremental, but distinguishable, effects on food consumption and meal parameters. Palatability mainly influences meal size, whereas variety exerts an effect on meal size and inter-meal interval. However, the potential effect of variety on overall intake is probably somewhat reduced by the tendency to eat only one type of food in each meal. Obesity has an inhibitory influence on feeding, operating primarily through a reduction in meal frequency.     

氯氮平和氟哌啶醇对慢性精神分裂症患者糖、脂代谢及体重变化的比较分析

目的 比较氯氮平和氟哌啶醇对慢性精神分裂症患者的血糖、血脂代谢及体重变化情况。方法 采用氯氮平（89例）和氟哌啶醇（87例）对慢性精神分裂症患者进行治疗,并于治疗前后不同时段作血糖、胰岛素、血脂和体重的测定,同时比较其浓度变化和进行相关性分析。结果 ①氯氮平组在用药的第3和第6个月末,血糖浓度异常发生率分别为7．9％及23．6％,氟哌啶醇组为1．1％和2．3％。②氯氮平组在用药第3个月末,空腹及餐后2小时血糖浓度均较基线值升高,第6个月末继续升高;而在氟哌啶醇组上述两个治疗时段的变化则不明显。③氯氮平组在用药的第3个月末,体重平均增高为治疗前的5．5％,第6个月末增高为治疗前的9．1％,而氟哌啶醇组则变化不明显,④两组患者在用药第6个月末,胰岛素浓度均高于基线值;氯氮平组的胆固醇和甘油三酯浓度均高于基线值,而氟哌啶醇组则无明显变化。⑤在用药第6个月时,氯氮平组血糖、胰岛素、血脂浓度、体重变化和血药浓度之间均有一定相关性（r=0．21～0．99）,差异均有统计学意义（P〈0．05或〈0．01）。结论氯氮平对慢性精神分裂症患者的糖、脂代谢和体重有影响,治疗期间需监测。     

Meal patterns and food selection during the development of obesity in rats fed a cafeteria diet

(1) Offering preferred foods in addition to laboratory chow led immediately to a marked increase in both mean meal size (MMS) and meal frequency (MF). (2) As body weight increased over a 5 months period, MF declined to a low level but MMS remained high. (3) Within a majority of meals there was substantial consumption of only one food item. Nonetheless, when “mixed” meals were eaten these were usually larger than “exclusive” meals. (4) With more than one preferred food available there was a significant tendency to alternate consumption of food types from one meal to the next. This disappeared at inter-meal intervals longer than 90 minutes. (5) With one preferred food available, only MMS (and not MF) was increased and the degree of hyperphagia and obesity were reduced. The findings suggest the following conclusions: Both palatability (preference value for a particular food) and variety (availability of different types of food) have incremental, but distinguishable, effects on food consumption and meal parameters. Palatability mainly influences meal size, whereas variety exerts an effect on meal size and inter-meal interval. However, the potential effect of variety on overall intake is probably somewhat reduced by the tendency to eat only one type of food in each meal. Obesity has an inhibitory influence on feeding, operating primarily through a reduction in meal frequency.     

Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake

The objective of the present study was to identify hypothalamic sites that might be implicated in the effects of neuropeptide Y (NPY) on both body temperature and food intake. For this purpose, the effects of direct microinjections of NPY in several doses (0.156–20 μg) into discrete hypothalamic nuclei on body temperature were examined in rats. To examine specificity of effects, food consumption of animals following injections was also measured. Results indicate that the influence of NPY on body temperature varies with the hypothalamic region where the peptide is administered. NPY had no effect on temperature after administration into the ventromedial (VMH) and the perifornical hypothalamus (PeF). However, a significant hypothermia was seen following administration into the preoptic (POA) and arcuate nucleus (Arc), and hyperthermia was seen after injection into the paraventricular nucleus (PVN). Finally, a biphasic effect was observed after injection into the lateral hypothalamus (LH): hyperthermia with relatively small doses and hypothermia with higher doses. Similar effects were obtained when administred into the third ventricle (3V) but in an inverted dose-related fashion: hypothermia at low and hyperthermia at higher doses. For feeding, NPY consistently increased food intake in all regions examined, with the strongest effect obtained after administration into the PeF. The present results clearly dissociate the effects of NPY on food intake and body temperature, and demonstrate that these effects are related to specific hypothalamic nuclei.     

Lateral hypothalamic lesions in ground squirrels: Rapid recovery and residual deficits

The effects of lateral hypothalamic (LH) lesions were studied in golden-mantled ground squirrels, Spermophilus lateralis, a species of mammalian hibernator that displays endogenous circannual body weight cycles when kept in constant conditions. The lesions were made during the weight-gain phase. Evidence that the lesions were well placed included interruption of weight gain, transient aphagia, disrupted nest building, increased spillage of food crumbs and in some cases abnormal postures or movement. Despite these deficits most animals survived. Their body weights at the first postoperative peak of the cycle recovered either to within the control range (Experiment 1) or close to preoperative peak levels (Experiment 2). There was no evidence that the lesions lowered set points. The rapid recovery of weight and eating by ground squirrels given only dry rodent chow, after large lesions (1.5-2.5 mA, DC anodal, 15-25 s), contrasts with what is seen in rats following LH lesions.     

Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus

Macro-electrophoretic applications of the cellular neurotoxin ibotenic acid into the ventromedial hypothalamic nucleus (VMH) resulted in hyperphagia and obesity in male rats. Histological examination showed a reduction in the number of neuronal VMH cell bodies with glial proliferation without evidence of non-specific damage. This supports the hypothesis that hyperphagia and obesity after VMH lesions are related to destruction of neurons intrinsic to the VMH.     

Paraventricular nucleus lesions exaggerate dietary obesity but block photoperiod-induced weight gains and suspension of estrous cyclicity in Syrian hamsters

Lesions of the paraventricular nucleus (PVN) of the hypothalamus block short photoperiod-induced testicular regression in Syrian hamsters. We examined the effects of PVN or sham lesions on the short photoperiod-induced increases in body weight and adiposity in female Syrian hamsters. PVN lesions did not affect body weight when hamsters were housed in a long photoperiod (LD, 16:8) and fed Purina laboratory rodent chow (No. 5001). However, when fed a high-fat diet both groups gained weight, and the hamsters with PVN lesions gained approximately twice as much as the sham-operated controls. When the hamsters were exposed to a short photoperiod (LD, 8:16), only the hamsters with sham lesions displayed the typical increase in body weight. No further increase in body weight or parametrial fat pad weight was seen when the hamsters with PVN lesions were exposed to the short photoperiod. The lack of a short photoperiod-induced increase in body weight gain in hamsters with PVN lesions seems unlikely to be due to a "ceiling effect" on body weight gain because we have routinely observed neurally intact, melatonin-treated female Syrian hamsters with body weight in excess of 250 g. Finally, the short photoperiod interrupted estrous cyclicity in sham-lesioned hamsters but not in those with PVN lesions. Thus, PVN lesions exaggerate dietary obesity but prevent short photoperiod-induced weight gains and vaginal acyclicity in female Syrian hamsters.     

Involvement of dopaminergic systems in the ventromedial hypothalamic hyperphagia

The effect of chronic dopamine receptor blockage on ventro-medial hypothalamic lesion induced hyperphagia and obesity was studied. Rats with electrolytic ventromedial hypothalamic (VMH) lesions were treated chronically with either haloperidol (DA antagonist) or vehicle solution. Food intake of rats with VMH lesions fell well below baseline levels. Additionally, these animals started losing body weight within 24 hours of the initiation of treatment and continued to lose weight throughout the treatment period. When the treatment was discontinued these animals resumed overeating and regained body weights. The food intakes and body weights of unlesioned rats treated with either haloperidol or vehicle, and VMH lesioned rats treated with vehicle, were not affected by these treatments.     

Effects of NPY and NPY2–36 on body temperature and food intake following administration into hypothalamic nuclei

Our previous in vivo structure-activity studies suggested that the putative receptors mediating the effects of NPY and NPY_2–36 on food intake and body temperature are pharmacologically different [17]. In the present study, we examined and compared dose-related effects of NPY and NPY_2–36 on ad lib food intake and rectal temperature after administration into discrete hypothalamic nuclei of the rat. Results indicate that NPY and NPY_2–36 have opposite effects on body temperature to those of NPY when injected in the preoptic area (POA): hypothermia and hyperthermia, respectively. When administered in the paraventricular nucleus (PVN), both increased body temperature. When injected into the third ventricle (3V), NPY produced a biphasic effect: hypothermia at low doses and hyperthermia at high doses. Similar effects were obtained with NPY_2–36, but in an inverted dose-related fashion: hyperthermia at low and hypothermia at higher doses. In the arcuate nucleus (Arc), NPY induced a significant hypothermia whereas NPY_2–36 had no effect. Finally, neither peptide affected body temperature when injected into the ventromedial (VMH) and perifornical (PeF) nuclei. Both NPY and NPY_2–36 increased food intake after injection in all regions examined. In general, NPY was more potent and efficacious than NPY_2–36. The present results clearly dissociate the effects of NPY on food intake and body temperature. Furthermore, the data support the hypothesis that the putative receptors underlying the effects of NPY and NPY_2–36 on food intake are similar, whereas those mediating the effects on body temperature are pharmacologically different.     

抗精神病药物对精神分裂症患者血脂、血糖和体重影响的研究

目的比较精神分裂症患者服用抗精神病药物后血脂、血糖及体重的变化,评价不同药物的安全性。方法选择109例单一应用抗精神病药物治疗满8周的精神分裂症患者,分别于第4周、第8周测量血脂(胆固醇、甘油三脂)、血糖和体重。结果服用抗精神病药物后女性、高龄患者甘油三脂增高显著,差异有统计学意义(t=-2.34,P<0.05;r=0.256,P=0.007);氯氮平对胆固醇升高影响显著高于利培酮、奎硫平、氯丙嗪、奋乃静等(P<0.05);氯氮平、氯丙嗪对甘油三脂升高影响显著高于利培酮(P<0·05);所有纳入研究的药物对血糖、体重有不同程度影响,差异无显著性(P>0.05)。结论大多数抗精神病药物可增加高血脂、肥胖的风险,选择药物应考虑性别及年龄因素。     

Central adaptation to chronic administration of interleukin-1beta (IL-1beta) in rats

Interleukin-1beta (IL-1beta), a cytokine, has been shown to induce a number of central and neuroendocrine effects. Prolonged treatment with IL-1beta is associated with adaptive responses in feeding, body temperature and hormone profiles. The purpose of the present study was to see if these effects are accompanied by changes in hypothalamic norepinephrine (NE) and to compare it with the acute effects of IL-1beta. Adult male Sprague-Dawley rats were treated (i.p.) with 5 microg of IL-1beta once (acute) or daily for 5 consequent days (chronic). The control animals received an injection of the vehicle for IL-1beta (0.1% PBS-BSA). Body weight, food intake, and rectal temperature were monitored daily. At the end of treatment, the animals were sacrificed, and specific areas of the hypothalamus were microdissected and analyzed for NE concentrations. Corticosterone levels were measured in the serum. Both acute and chronic IL-1beta treatment produced significant changes in a number of parameters. However, there were marked differences between the two treatment regimens. While acute treatment with IL-1beta increased NE concentrations in both the paraventricular nucleus and the median eminence (ME), chronic treatment increased NE concentrations only in the ME. A corresponding increase in serum corticosterone levels was observed with acute IL treatment. Chronic treatment with IL-1beta decreased body weight, and produced an initial decrease in food intake which returned to control levels by the fourth day of treatment. Chronic IL treatment also produced an initial increase in body temperature that returned to control levels by day 4. These results indicate that the effects of IL-1beta on central and neuroendocrine functions are dependent on the duration of the treatment and that the adaptive responses observed in feeding and body temperature after chronic IL treatment are accompanied by similar responses in brain NE.     

Neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level are increased in the hypothalamus of mouse bearing a human oral squamous cell carcinoma

We examined gene expression of corticotropin-releasing hormone and neuropeptide Y level in the hypothalamic paraventricular nucleus of mouse bearing a human oral squamous cell carcinoma. A cell line derived from a human oral squamous cell carcinoma was inoculated into the lower dorsal area of nude mice. Body weight, tumor size and daily food intake were recorded every morning. Mice were sacrificed for corticotropin-releasing hormone mRNA in situ hybridization and neuropeptide Y immunohistochemistry, when the tumor ratio reached to 11-13% of real body weight. The results were compared with the age-matching non-tumor controls injected with saline instead of carcinoma cell. Body weight gain was significantly reduced in tumor bearing mice, however, no compensatory hyperphagia was found, i.e. daily food intake of the tumor mice did not differ from the non-tumor mice. Both neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level were significantly increased in the hypothalamic paraventricular nucleus of tumor mice. These results suggest that a human oral squamous cell carcinoma may induce anorexia, at least partly, via increasing the hypothalamic expression of corticotropin-releasing hormone in the tumor subjects. Additionally, neuropeptide Y-induced feeding appears to be inhibited in this tumor anorexia model, and this may correlate with increased expression of corticotropin-releasing hormone.     

The effects of serotonin1A receptor on female mice body weight and food intake are associated with the differential expression of hypothalamic neuropeptides and the GABAA receptor

Both common eating disorders anorexia nervosa and bulimia nervosa are characteristically diseases of women. To characterize the role of the 5-HT_1A receptor (5-HT_1A-R) in these eating disorders in females, we investigated the effect of saline or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) treatment on feeding behavior and body weight in adult WT female mice and in adult 5-HT_1A-R knockout (KO) female mice. Our results showed that KO female mice have lower food intake and body weight than WT female mice. Administration of 8-OH-DPAT decreased food intake but not body weight in WT female mice. Furthermore, qRT-PCR was employed to analyze the expression levels of neuropeptides, γ-aminobutyric acid A receptor subunit β (GABA_A β subunits) and glutamic acid decarboxylase in the hypothalamic area. The results showed the difference in food intake between WT and KO mice was accompanied by differential expression of POMC, CART and GABA_A β2, and the difference in body weight between WT and KO mice was associated with significantly different expression levels of CART and GABA_A β2. As such, our data provide new insight into the role of 5-HT_1A-R in both feeding behavior and the associated expression of neuropeptides and the GABA_A receptor.     

利培酮与喹硫平对老年期痴呆患者体重及糖脂代谢的影响

目的探讨利培酮与喹硫平对伴精神行为症状的老年期痴呆患者（BPSD）的体重、血糖及血脂的影响。方法将60例伴精神行为症状的老年期痴呆患者分为喹硫平组及利培酮组进行治疗,于治疗前及治疗后（第4、8周末）分别测体重、空腹血糖及血脂包括胆固醇（TC）、甘油三脂（TG）、低密度脂蛋白（LDL）及高密度脂蛋白（HDL）。结果喹硫平组的体重及LDL在治疗第8周末较治疗前升高,HDL较治疗前下降,差异具有显著性（P〈0.05）。利培酮组治疗前后各数值的变化无显著差异（P〉0.05）。两组患者体重的第8周末与治疗前差值,LDL的第8周末与第4周末的差值比较有统计学意义（P〈0.05）。结论喹硫平对伴精神行为症状的痴呆患者体重、血脂的影响较利培酮明显,两者对糖代谢影响不大。     

Suprachiasmatic nucleus: role in circannual body mass and hibernation rhythms of ground squirrels

Female golden-mantled ground squirrels that sustained complete ablation of the suprachiasmatic nucleus (SCNx) were housed pre- and post-operatively at 23°C and then at 6.5°C for 5–7 yr. SCNx and control animals held at the higher temperature manifested circannual rhythms (CARs) in body mass. In contrast, body mass CARs were not expressed in 50% of SCNx squirrels during cold exposure; rhythm amplitude was reduced to 25–40% of pre-operative values and the interval between successive peaks in body mass fell outside the circannual range. Unlike normal squirrels that hibernate for about 6 months during each circannual cycle, these SCNx squirrels expressed bouts of torpor nearly continuously throughout 2.5 yr of cold exposure. Body mass increases were often observed during hibernation—a phenomenon never observed in control animals. The remaining SCNx squirrels that did not hibernate continuously displayed CARs in body mass within the normal range. The effects of SCN ablation on body mass rhythms presumably are related to disrupted patterns of hibernation, food intake, and metabolism. The SCN, which sustains neural and metabolic activity at low tissue temperatures, may exert greater influence on thermoregulation and metabolism during the hibernation season than at other times of year, thereby accounting for the greater effect of SCN ablation in squirrels maintained at low ambient temperatures.