Adam R. Kennedy

Blockade of the neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(3-36) on food intake.

The gastrointestinal-derived hormone peptide YY (PYY) is released from intestinal L-cells post-prandially in proportion to calorie intake, and modulates food intake. Peripheral administration of PYY((3-36)) reduces food intake and body weight in rodents and suppresses appetite and food intake in humans. PYY((3-36)) is hypothesised to inhibit food intake via activation of the auto-inhibitory pre-synaptic neuropeptide Y (NPY) Y2 receptor (Y2R) present on arcuate (ARC) NPY neurons. We aimed to investigate the feeding effect of PYY((3-36)) following blockade of ARC Y2R, using the specific receptor antagonist BIIE0246, in the rat. We found that pre-treatment with BIIE0246 (1 nmol) into the ARC attenuated the reduction in feeding observed following intraperitoneal injection of PYY((3-36)) (7.5 nmol/kg) (0-1 h food intake: BIIE0246/PYY((3-36)): 3.8 +/- 0.4 g; vs. Vehicle/PYY((3-36)): 2.7 +/- 0.2 g; P < 0.05). We found plasma PYY levels to be maximal at 120 min post-initiation of feeding. On investigation of the endogenous role of the Y2R, we found that ARC administration of BIIE0246 alone significantly increased feeding in satiated rats compared to vehicle-injected controls (0-1 h food intake: BIIE0246: 4.1 +/- 0.7 g; vs. vehicle: 1.7 +/- 0.7 g; P < 0.05), suggesting that Y2R antagonism disinhibits the NPY neuron thus stimulating feeding in otherwise satiated rats. These studies suggest that the Y2R plays an important role in post-prandial satiety and provide further insight into the mechanisms of action of PYY((3-36)).

Chronic CNS administration of Agouti-related protein (Agrp) reduces energy expenditure

OBJECTIVE: To investigate whether the Agouti-related protein (Agrp), the melanocortin receptor antagonist, alters oxygen consumption, as a measure of energy expenditure.DESIGN: A 7-day intracerebroventricular administration of Agrp (1 nmol/day) in rats.MEASUREMENTS: Oxygen consumption was determined in closed-circuit respirometers on days 1 and 8. BRL-35135, a β3-adrenoreceptor agonist known to activate the brown adipose tissue (BAT) thermogenesis directly and increase core temperature, was administered i.p. (40 μg/kg) on day 9 to challenge functionally the BAT.RESULTS: Agrp treatment caused a 54% increase in daily food intake and a 12% increase in body weight. An 8% decrease in VO2 measurements was observed following ICV Agrp treatment on day 1. A similar decrease (7%) was observed on day 8. BRL-35135 stimulated colonic temperature in control rats. However, in the rats that had previously been treated with Agrp this effect was significantly blunted.CONCLUSION: Chronic CNS administration of Agrp decreases oxygen consumption and decreases the capacity of BAT to expend energy. The obesity observed following CNS administration of Agrp is the result of decreased energy expenditure and increased food intake.

Prolactin-Releasing Peptide Releases Corticotropin-Releasing Hormone and Increases Plasma Adrenocorticotropin via the Paraventricular Nucleus of the Hypothalamus

Intracerebroventricular (ICV) injection of prolactin-releasing peptide (PrRP) is known to increase plasma adrenocorticotropin (ACTH) and cause c-fos expression in the hypothalamic paraventricular nucleus (PVN). We hypothesize that this is the site at which PrRP acts to increase plasma ACTH. We have used ICV injection and direct intranuclear injection of PrRP into the PVN to investigate the sites important in the stimulation of ACTH release in vivo. To investigate the mechanism of action by which PrRP increases ACTH, we have used primary culture of pituitary cells and measured neuropeptide release from in vitro hypothalamic incubations. ICV administration of PrRP increased plasma ACTH 10 min post-injection (PrRP 5 nmol 81.0 ± 23.5 pg/ml vs. saline 16.8 ± 14.1 pg/ml, p < 0.05). Intra-PVN injection of PrRP increased ACTH 5 min post-injection (PrRP 1 nmol 22.9 ± 5.0 pg/ml vs. saline 10.3 ± 1.4 pg/ml, p < 0.05). This effect continued until 40 min post-injection (PrRP 1 nmol 9.9 ± 1.5 pg/ml vs. saline 6.2 ± 0.5 pg/ml, p < 0.05). In vitro PrRP (1–100 nmol/l) did not effect basal or corticotropin-releasing hormone (CRH)-stimulated ACTH release from dispersed anterior pituitary cells. PrRP increased hypothalamic release of CRH (PrRP 100 nmol/l 1.4 ± 0.2 nmol/explant vs. the basal 1.1 ± 0.2 nmol/explant, p < 0.05) but not arginine vasopressin. PrRP also stimulated neuropeptide Y release (PrRP 100 nmol/l 56.5 ± 11.8 pmol/explant vs. basal 24.0 ± 1.9 pmol/explant, p < 0.01), a neuropeptide known to stimulate the hypothalamo-pituitary-adrenal axis. Our data suggest that in vitro PrRP does not have a direct action on the corticotrope but increases plasma ACTH via the PVN and this effect involves the release of hypothalamic neuropeptides including CRH and neuropeptide Y.