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Male C57BL/6 mice fed ad libitum on control diet but allowed access to a palatable high fat diet (HFD) for 2 h a day during the mid-dark phase rapidly adapt their feeding behaviour and can consume nearly 80% of their daily caloric intake during this 2 h-scheduled feed. We assessed food intake microstructure and meal pattern, and locomotor activity and rearing as markers of food anticipatory activity (FAA). Schedule fed mice reduced their caloric intake from control diet during the first hours of the dark phase but not during the 3-h period immediately preceding the scheduled feed. Large meal/binge-like eating behaviour during the 2-h scheduled feed was characterised by increases in both meal number and meal size. Rearing was increased during the 2-h period running up to scheduled feeding while locomotor activity started to increase 1 h before, indicating that schedule-fed mice display FAA. Meal number and physical activity changes were sustained when HFD was withheld during the anticipated scheduled feeding period, and mice immediately binged when HFD was represented after a week of this "withdrawal" period. These findings provide important context to our previous studies suggesting that energy balance systems in the hypothalamus are not responsible for driving these large, binge-type meals. Evidence of FAA in HFD dark phase schedule-fed mice implicates anticipatory processes in binge eating that do not involve immediately preceding hypophagia or regulatory homeostatic signalling., (Copyright © 2014. Published by Elsevier Ltd.)

Providing rats and mice with access to palatable high fat diets for a short period each day induces the consumption of substantial binge-like meals. Temporal food intake structure (assessed using the TSE PhenoMaster/LabMaster system) and metabolic outcomes (oral glucose tolerance tests [oGTTs], and dark phase glucose and insulin profiles) were examined in Sprague-Dawley rats given access to 60% high fat diet on one of 3 different feeding regimes: ad libitum access (HF), daily 2 h-scheduled access from 6 to 8 h into the dark phase (2 h-HF), and twice daily 1 h-scheduled access from both 1-2 h and 10-11 h into the dark phase (2×1 h-HF). Control diet remained available during the scheduled access period. HF rats had the highest caloric intake, body weight gain, body fat mass and plasma insulin. Both schedule-fed groups rapidly adapted their feeding behaviour to scheduled access, showing large meal/bingeing behaviour with 44% or 53% of daily calories consumed from high fat diet during the 2 h or 2×1 h scheduled feed(s), respectively. Both schedule-fed groups had an intermediate caloric intake and body fat mass compared to HF and control (CON) groups. Temporal analysis of food intake indicated that schedule-fed rats consumed large binge-type high fat meals without a habitual decrease in preceding intake on control diet, suggesting that a relative hypocaloric state was not responsible or required for driving the binge episode, and substantiating previous indications that binge eating may not be driven by hypothalamic energy balance neuropeptides. In an oGTT, both schedule-fed groups had impaired glucose tolerance with higher glucose and insulin area under the curve, similar to the response in ad libitum HF fed rats, suggesting that palatable feeding schedules represent a potential metabolic threat. Scheduled feeding on high fat diet produces similar metabolic phenotypes to mandatory (no choice) high fat feeding and may be a more realistic platform for mechanistic study of diet-induced obesity., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this article was to examine associations between specific dimensions of nursing home environments and the functional ability (walking and eating) of residents with dementia, and to contribute to the ongoing psychometric development of the Professional Environmental Assessment Protocol (PEAP)., Design: One-year prospective cohort study., Setting: Fifteen nursing homes in a western Canadian province., Participants: Convenience sample of 120 nursing home residents with middle-stage dementia., Measurements: Every 2 weeks we observed residents' abilities to walk to the dining room and to feed themselves. At the end of a year of observation and immediately following a brief interview with the unit managers, we used the PEAP to measure the extent to which 9 specific dimensions of nursing home environments support the ability of residents with dementia to walk and to eat. Cox proportional hazards models were used to evaluate the effect of specific environmental features on residents' walking and eating disability., Results: "Support of functional ability" was associated with a reduced hazard of both walking and eating disability. The environmental dimensions of "maximizing awareness and orientation" and better "quality of stimulation" were associated specifically with reduced hazard of walking disability, whereas the dimensions of the nursing home environment specifically associated with a reduced hazard of eating disability included improved "safety and security," "opportunities for personal control," and "regulation of stimulation." The Cox proportional hazards models using the 13-point PEAP scale were not significantly different from nested models using the 5-point PEAP scale, indicating that the 2 scales did not differ in their ability to discriminate between more and less supportive environments for residents with dementia., Conclusions: Specific dimensions of the nursing home environment reduced the hazard of walking disability, whereas others reduced the hazard of eating disability. Modifying specific features of nursing home environments may reduce disability in nursing home residents with dementia. The 5-point PEAP scale is able to discriminate between nursing home environments as well as the 13-point scale., (Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure. To examine the effects of rimonabant on components of energy balance, we administered rimonabant or its vehicle to diet-induced obese (DIO) C57BL/6 mice once daily for 30 days, by oral gavage. Rimonabant induced a persistent weight reduction and a significant decrease in body fatness across all depots. In addition to transiently reduced food intake, rimonabant-treated mice exhibited decreased apparent energy absorption efficiency (AEAE), reduced metabolizable energy intake (MEI), and increased daily energy expenditure (DEE) on days 4-6 of treatment. However, these effects on the energy budget had disappeared by days 22-24 of treatment. No chronic group differences in resting metabolic rate (RMR) or respiratory quotient (RQ) (P > 0.05) were detected. Rimonabant treatment significantly increased daily physical activity (PA) levels both acutely and chronically. The increase in PA was attributed to elevated activity during the light phase but not during the dark phase. Taken together, these data suggested that rimonabant caused a negative energy balance by acting on both energy intake and expenditure. In the short term, the effect included both reduced intake and elevated PA but the chronic effect was only on increased PA expenditure.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be important in physiological regulation of food intake. We investigated which hypothalamic areas known to express MC4R are involved in the regulation of feeding by using alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R antagonist. Cannulae were inserted into the rat hypothalamic paraventricular (PVN), arcuate (Arc), dorsomedial (DMN), and ventromedial (VMN) nuclei; the medial preoptic (MPO), anterior hypothalamic (AHA), and lateral hypothalamic (LHA) areas; and the extrahypothalamic central nucleus of the amygdala (CeA). Agrp (83-132) (0.1 nmol) and [Nle4, D-Phe7]alpha(-MSH (NDP-MSH) (0.1 nmol), a stable alpha-MSH analog, were administered to fed and fasted rats, respectively. The PVN, DMN, and MPO were the areas with the greatest response to Agrp and NDP-MSH. At 8 h postinjection, Agrp increased feeding in the PVN by 218 +/- 23% (P < 0.005), in the DMN by 268 +/- 42% (P < 0.005), and in the MPO by 236 +/- 31% (P < 0.01) compared with a saline control group for each nucleus. NDP-MSH decreased food intake in the PVN by 52 +/- 6% (P < 0.005), in the DMN by 44 +/- 6% (P < 0.0001), and in the MPO by 55 +/- 6% (P < 0.0001) at 1 h postinjection. Injection into the AHA and CeA resulted in smaller alterations in food intake. No changes in feeding were seen after the administration of Agrp into the Arc, LHA, or VMN, but NDP-MSH suppressed food intake in the Arc and LHA. This study indicates that the hypothalamic nuclei expressing MC4R vary in their sensitivity to Agrp and alpha-MSH with regard to their effect on feeding.

Melanin concentrating hormone (MCH) is recognised as a hypothalamic appetite stimulant. The mechanism of action of MCH is undetermined largely due to lack of identification of hypothalamic MCH receptors. We designed in vivo and in vitro studies to further characterise the feeding effects of MCH in the rat. MCH was injected directly into the paraventricular nucleus (PVN) at the beginning of the light phase. PVN MCH (0.5 microg) produced an increase in 2 h food intake of 272+/-60% vs. saline control (0.7+/-0.2 g), p<0.05. The time course of the effect of intracerebroventricular (i.c.v.) administration of 5 microg MCH on food intake was investigated. An increase in feeding was observed within 15 min from the time of injection and was not sustained beyond half an hour following administration. To investigate a possible interaction with galanin, 5 microg of MCH was injected i.c.v. with or without 10 microg of galanin. The two peptides together increased 1 h feeding above that of either peptide alone, 768+/-62% (compared with the saline group, 0.47+/-0.2 g), p<0.05 vs. 585+/-36%, galanin alone and 317+/-72%, MCH alone. Finally, to investigate if MCH bound to the brain melanocortin receptors, receptor autoradiography was performed on rat brain sections with the stable analogue of alpha MSH, [125I] Nle(4), D-Phe(7)-alphaMSH and unlabeled MCH. MCH did not compete with [125I] Nle(4), D-Phe(7)-alphaMSH binding. Results demonstrate that MCH stimulates feeding via the PVN, has a short onset and duration of action and activates feeding by mechanisms independent to galanin and the melanocortin receptors.

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.

We have previously shown that intracerebroventricular BIBP 3226 inhibits NPY induced feeding in rats. However, this was associated with abnormal behaviour, likely to be due to interaction with Y1 receptors involved in mechanisms other than the control of food intake. In order to minimise such interactions we investigated the effects of paraventricular nucleus (PVN) injections of BIBP 3226 and its inactive enantiomer BIBP 3435. Intra-PVN injection of NPY (0.1-2.5 nmol/animal) increased food intake, with an EC50 of approximately 0.15 nmol/animal. Injections of BIBP 3226 and BIBP 3435 (0.25-25 nmol) reduced NPY-induced food intake in a dose responsive manner, with BIBP 3226 reducing food intake by 95%, and BIBP 3435 by 65% at the highest dose tested. The reversibility of the effect of BIBP 3226 was investigated by measuring the feeding response to NPY (0.5 nmol) in animals 1 week after BIBP 3226 injection. The response to NPY was less in animals which had received high doses of BIBP 3226. Animals previously injected with saline vehicle alone showed a normal NPY feeding response. These results suggest that BIBP 3226 may be inhibiting NPY-induced food intake in a non-specific manner, not secondary to inhibition of the Y1 receptor. This does not, however rule out a role for the Y1 receptor in the control of food intake by NPY.

There are now six recognized neuropeptide Y (NPY) receptor subtypes (Y1-Y4 and two recently cloned distinct receptors labeled Y5), of which Y1 and one of the Y5's have been suggested could mediate the effect of NPY on feeding. The fragments NPY(2-36) and NPY(3-36), which bind Y1 only poorly, were injected intracerebroventricularly (icv) and found to have similar dose-response relationships to NPY in the stimulation of feeding. However NPY (13-36), which stimulates both Y2 and Y5, caused no increase in food intake, even at high doses. Maximal stimulation with the classical Y1 agonist [Pro34]-NPY produced only 50% of the maximum effect of NPY itself despite fully inhibiting adenylyl cyclase activity in vitro in a Y1 system. The novel fragment [Pro34]-NPY(3-36) is as effective at stimulating food intake as the classical Y1 analogue [Pro34]-NPY but bound to the Y1 receptor with only 1/20th of the affinity of NPY and failed to inhibit adenylyl cyclase through this receptor. [Pro34]-NPY(3-36) is therefore a relatively appetite-selective ligand. Coadministration of high dose NPY(13-36) and [Pro34]NPY did not enhance feeding compared with [Pro34]-NPY alone. In addition, the NPY Y1 receptor antagonist BIBP-3226, which does not bind Y2, Y4, or Y5 receptors, significantly reduced NPY induced feeding. These results indicate that the feeding effect of icv NPY involves a novel receptor and that it is functionally distinct from the recognized receptor subtypes.

Concentrations of the potent hypothalamic appetite stimulating peptide neuropeptide Y (NPY), and its mRNA, are increased in rats with experimental diabetes, suggesting a role in the hyperphagia of this disorder. The 2-h feeding responses to intracerebroventricular (i.c.v.) injection of neuropeptide Y (NPY) (5, 10, and 15 mu g doses) were measured in male Wistar rats treated with streptozotocin (55 mg/kg) to induce diabetes. Streptozotocin-diabetic rats given i.c.v. NPY exhibited reduced feeding responses compared to controls (P < 0.05). Dexamethasone treated rats exhibit similar changes in NPY content and mRNA in the hypothalamus to those seen in diabetes, but are not hyperphagic. Feeding responses were also measured in this model, to assess whether high levels of endogenous NPY might account for the reduced response in diabetes. In contrast, the feeding response to NPY in comparison to controls was unaltered in dexamethasone treated rats. To investigate whether altered NPY receptor number or affinity, was the underlying mechanism for these divergent responses, receptor binding experiments were performed using (125)I-PYY and membranes prepared from rat hypothalamus. No significant difference was found in receptor number or affinity between the 2 groups (B(max): 114.7 +/- 18.9 vs 127.4 +/- 27.1 fmol/mg protein, K(d): 99.6 +/- 28.2 vs 135.1 +/- 32.4 pM). Similarly no difference was found between hypothalamic membranes prepared from dexamethasone-treated and control animals. NPY receptor subtypes in the hypothalamus were compared with that of cortex (predominantly Y1) and hippocampus (predominantly Y2) using the Y1-specific ligand [Leu(31)Pro(34)] NPY. These studies showed that the binding profile in the hypothalamus most closely matched that in the hippocampus, suggesting that the majority of hypothalamic receptors were of the Y2 subtype. Receptor autoradiography revealed low binding in the hypothalamus, and particularly in the paraventricular nucleus of the hypothalamus. Competition with [Leu(31)Pro(34)] NPY confirmed that only a low density of binding to Y1 like receptors was present in the hypothalamus. No difference was observed between control and streptozotocin treated animals. The feeding response to exogenous NPY is reduced in experimental diabetes, but not in dexamethasone treated rats. These differing responses do not appear to be due to altered NPY receptor number or affinity in the hypothalamus.