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Objective: The hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU)., Results: Our results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide., Conclusion: We have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.

Background: Oxyntomodulin has recently been found to decrease body-weight in obese humans and may be a potential anti-obesity therapy., Objective: To determine whether oxyntomodulin alters energy expenditure, in addition to reducing energy intake, in 'free-living' overweight and obese volunteers., Design: Randomized double-blind controlled cross-over trial., Setting: Community and hospital-based., Participants: Fifteen healthy overweight and obese men and women (age: 23-49 years, BMI: 25.1-39.0 kg/m(2)). All volunteers completed the study protocol., Interventions: Four-day subcutaneous self-administration of pre-prandial oxyntomodulin, three times daily. Participants were advised to maintain their normal dietary and exercise regimen., Measurements: (1) Energy expenditure, measured by indirect calorimetry and combined heart rate and movement monitoring; (2) energy intake, measured during a study meal., Results: Oxyntomodulin administration reduced energy intake at the study meal by 128+/-29 kcal (P=0.0006) or 17.3+/-5.5% (P=0.0071), with no change in meal palatability. Oxyntomodulin did not alter resting energy expenditure; but increased activity-related energy expenditure by 143+/-109 kcal/day or 26.2+/-9.9% (P=0.0221); total energy expenditure by 9.4+/-4.8% (P=0.0454) and physical activity level by 9.5+/-4.6% (P=0.0495). A reduction in body weight of 0.5+/-0.2% was observed during the oxyntomodulin administration period (P=0.0232)., Conclusion: Oxyntomodulin increases energy expenditure while reducing energy intake resulting in negative energy balance. This data supports the role of oxyntomodulin as a potential anti-obesity therapy.

Objective: Abnormalities of the melanocortin system produce obesity and increased linear growth. While the obesity phenotype is well characterised, the mechanism responsible for increased linear growth is unclear. The somatotrophic axis was studied in the obese agouti (A(y)/a) mouse as a model of a perturbed melanocortin system., Design: Adult obese A(y)/a mice were compared to age- and sex-matched wild-type (WT) controls. Weight and body length (nose-anus) were recorded. Plasma growth hormone (GH), insulin-like growth factor-I (IGFI), insulin and leptin were measured using radioimmunoassay. Since ghrelin is a potent GH secretagogue, plasma ghrelin, stomach ghrelin peptide and stomach ghrelin mRNA expression were studied. Hypothalamic periventricular (PeVN) somatostatin neurones and arcuate (Arc) neuropeptide Y (NPY) neurones inhibit the growth axis, whereas Arc growth hormone-releasing hormone (GHRH) neurones are stimulatory. Therefore, specific hypothalamic expression of somatostatin, NPY and GHRH was measured using quantitative in situ hybridisation., Results: Obese A(y)/a mice were significantly heavier and longer than WT controls. Plasma IGFI concentrations were 30% greater in obese A(y)/a mice. Obese A(y) /a mice were hyperinsulinaemic and hyperleptinaemic, yet plasma ghrelin, and stomach ghrelin peptide and mRNA were significantly reduced. In obese A(y)/a mice, PeVN somatostatin and Arc NPY mRNA expression were reduced by 50% compared to WT controls, whereas Arc GHRH mRNA expression was unchanged., Conclusion: Increased body length in adult obese A(y)/a mice may result from reduced Arc NPY and PeVN somatostatin mRNA expression, which in turn, may increase plasma IGFI concentrations and upregulate the somatotrophic axis.

Background: The gastric hormone ghrelin appears a useful agent to stimulate food intake in people with anorexia of illness. The loss of ghrelin's acyl group renders it inactive, thus it has been thought that subcutaneous administration may be problematic., Objective: To investigate whether human subjects are sensitive to the effects of ghrelin administered by single subcutaneous injection., Study Design: Randomized, double-blind, placebo-controlled trial., Subjects: Sixteen healthy lean volunteers (eight men and eight women)., Protocol: Fasted subjects received subcutaneous injections of ghrelin (3.6 nmol/kg) or saline. After 30 min, a buffet breakfast was served., Results: Ghrelin injection increased energy intake by 27% (ghrelin 5076 +/- 691 kJ versus saline 4230+/-607 kJ, P = 0.04). Ghrelin appeared to enhance the perceived palatability of the food offered (palatability score: ghrelin 81.1 +/- 3.6 versus saline 70.0 +/- 4.4; P = 0.03)., Conclusions: These results suggest that subcutaneous ghrelin is effective at stimulating energy intake and improving palatability and may be of direct use in the treatment of appetite loss.

Objective: Peptide YY3-36 (PYY(3-36)), glucagon-like peptide-1 (GLP-1), oxyntomodulin and cholecystokinin (CCK) are gastrointestinal-derived hormones that are released postprandially in proportion to the amount of calories ingested. All significantly reduce food intake following peripheral administration to rodents. We have investigated the effect of handling, exposure to a novel environment or to environmental enrichment on the anorectic effect of these gut hormones., Results: Results suggest that the transfer of a rat into a novel environment (cage change) inhibits the anorectic response to peripherally administered PYY(3-36) and oxyntomodulin (1 h food intake reduction (% saline control): PYY/home cage 82.3 +/- 5.9%, P < 0.05; PYY/clean cage 103.4 +/- 9.7%; oxyntomodulin/home cage 71.6 +/- 12.1%, P < 0.05; oxyntomodulin/clean cage 103.0 +/- 8.5%) and attenuates the anorectic response to GLP-1 and CCK (1 h food intake reduction (% saline control): GLP-1/home cage 68.8 +/- 6.4%, P < 0.01; GLP-1/clean cage 80.0 +/- 9.3%; CCK/home cage 49.8 +/- 6.2%, P < 0.001; CCK/clean cage 69.4 +/- 10.6%, P < 0.05). We have also observed that exposure to a novel environment does not alter anorectic effect of peripherally administered melanocortin 3/4 receptor agonist, melanotan II (MTII) (1 h food intake reduction (% saline control): MTII/home cage 32.0 +/- 6.3%, P < 0.001; MTII/clean cage 24.8 +/- 4.2%, P < 0.001). The attenuation in food intake observed following exposure to a novel environment can be attributed, in part, to a significant reduction in the food intake of the saline treated animals. In a further study, the anorectic effect of peripherally administered PYY(3-36) is attenuated in unhandled rats (88 +/- 4.2% saline control, P = ns) or rats exposed to environmental enrichment (103.3 +/- 9.7% saline control, P = ns), but not in animals that were handled extensively prior to the study (80.1 +/- 7.3% saline control, P < 0.05)., Conclusion: These studies highlight the importance of handling, acclimatisation and habituation of rodents to experimental conditions prior to investigating the ability of gut hormones to alter food intake.