Kisspeptin is the peptide product of the KiSS-1 gene and the endogenous agonist for the GPR54 receptor. Recent evidence suggests the kisspeptin/GPR54 system is a key regulator of the reproductive system. We examined the effect of intracerebroventricular (i.c.v.) and peripheral administration of the active kisspeptin fragment, kisspeptin-10, on circulating gonadotropins and total testosterone levels in adult male rats. The effect of kisspeptin-10 in-vitro on the release of hypothalamic peptides from hypothalamic explants and gonadotropins from anterior pituitary fragments was also determined. The i.c.v. administration of kisspeptin-10 dosedependently increased plasma luteinizing hormone (LH) and increased plasma follicle stimulating hormone (FSH) and total testosterone at 60 mins post-injection. In a separate study investigating the time course of this response, i.c.v. administered kisspeptin-10 (3nmol) significantly increased plasma LH at 10, 20 and 60 mins, FSH at 60 mins and total testosterone at 20 and 60 mins post-injection. Kisspeptin-10 stimulated the release of luteinizing hormone releasing hormone (LHRH) from invitro hypothalamic explants. Peripheral administration of kisspeptin-10 increased plasma LH, FSH and total testosterone. However, doses of 100-1000nM kisspeptin-10 did not influence LH or FSH release from pituitary fragments in-vitro. Kisspeptin therefore potently stimulates the hypothalamic-pituitary-gonadal (HPG) axis. These effects are likely to be mediated via the hypothalamic LHRH system. 2 IntroductionKisspeptin is a 54 amino acid peptide encoded by the tumour suppressor gene KiSS-1(1-4). Kisspeptin is thus also known as 'metastin' because of its antimetastatic properties (4,5). Using quantitative polymerase chain reaction, KiSS-1 mRNA expression has been demonstrated in the placenta and throughout the central nervous system (CNS), including the hypothalamus (3). Endogenous forms of kisspeptin 54, 14 and 13 amino acids in length have been isolated from human placenta. The common C terminal decapeptide shared by these forms, kisspeptin-10, is secreted by cultured human trophoblasts (6). In humans, circulating kisspeptin levels are 7000-fold higher than basal levels during the third trimester of pregnancy (7).All kisspeptin fragments, including kisspeptin-10, have a similar affinity and efficacy for the previously orphan G-protein-coupled receptor, GPR54 (1). GPR54 was originally isolated from rat brain (8) and is highly expressed in the rat and human CNS and peripheral tissues (1,8). GPR54 receptor mRNA is expressed in several rat brain regions, with highest expression in the hypothalamus and amygdala. Within the hypothalamus, GPR54 mRNA is highly concentrated in the arcuate nucleus, the lateral hypothalamic area and the dorsomedial nucleus (8). In the periphery it is highly expressed in the pituitary, placenta and pancreas (1,3). Peripheral administration of kisspeptin-10 increases plasma oxytocin levels in female rats (1).Recent reports suggest that the kisspeptin/GPR54 system is a...

To determine whether peptide YY (PYY), ghrelin, glucose-dependent insulinotropic polypeptide (GIP), and satiety responses to food intake are impaired in anorexia or obesity, we studied 30 female adolescents with anorexia nervosa [body mass index (BMI) 16.3 kg/m2], obesity (BMI 34.3 kg/m2), or normal weight (BMI 20.2 kg/m2). PYY, ghrelin, GIP, insulin, and glucose concentrations and four markers of satiety were measured for 240 min after a mixed meal. The area under the curve for glucose was similar in obese (OB) and normal-weight control (C) subjects but was 15% lower in anorexic (AN) subjects. The area under the curve for insulin was 47% lower in AN and 87% higher in OB subjects, compared with C subjects. After the meal, PYY increased significantly in C (+41%, P < 0.05) but not in AN or OB adolescents. Ghrelin concentrations were highest in AN subjects and lowest in the OB group, compared with C subjects and fell significantly by 25% in all three groups. GIP concentrations were lower in AN subjects throughout the test and increased in all three groups after the mixed meal. AN adolescents reported being less hungry than OB and C adolescents. There was a negative correlation between fasting ghrelin (but not PYY or GIP) and BMI and insulin (r2= 0.33) and a positive correlation between the decrease in hunger 15 min after the meal and PYY concentrations at 15 min (r2= 0.20). In conclusion, the blunted PYY response to a meal in OB adolescents suggests that PYY plays a role in the pathophysiology of obesity. Ghrelin is unlikely to play a causal role in anorexia nervosa or obesity. The lower GIP observed in AN subjects despite a similar caloric intake may appropriately prevent an excessive insulin response in these patients.

Background-Short bowel patients with a

SUMMARY Refeeding starved rats with an elemental diet resulted in a marked increase in crypt cell production rate (CCPR) in the proximal small intestine but not in the distal regions of the gut. Little effect on CCPR was noted when inert bulk (kaolin) was added to the elemental diet. Addition of a poorly fermentable dietary fibre (purified wood cellulose) had little effect on intestinal epithelial cell proliferation except in the distal colon where it significantly increased CCPR. A more readily fermentable fibre (purified wheat bran) caused a large proliferative response in the proximal, mid, and distal colon and in the distal small intestine. A gel forming fibre only significantly stimulated proliferation in the distal colon; the rats in this group, however, did not eat all the food given. There was no significant correlation between CCPR and plasma gastrin concentrations, but plasma enteroglucagon concentrations were significantly correlated with CCPR in almost all the sites studied. Plasma PYY concentrations also showed some correlation with CCPR, especially in the colon. Thus while inert bulk cannot stimulate colonic epithelial cell proliferation fermentable fibre is capable of stimulating proliferation in the colon, and especially in the distal colon: it can also stimulate proliferation in the distal small intestine and it is likely that plasma enteroglucagon may have a role to play in this process.

The N-terminal fragment (PACAP 27) of the novel neuropeptide, pituitary adenylate cyclase-activating polypeptide 38 (PACAP 38), has 68% homology with vasoactive intestinal polypeptide (VIP). The administration of bolus doses of PACAP 38 and its 27 amino acid N-terminal fragment (PACAP 27) caused a rapid but transient dose-dependent hypotensive effect in the anaesthetized rat. The amplitude and duration of the response obtained by PACAP 38 was comparable with VIP whereas PACAP 27 was three times less potent than VIP. Furthermore, radioreceptor binding studies demonstrated that 125I-labelled PACAP 27 and 125I-labelled VIP bound to membranes prepared from blood vessels. Both PACAP 27 and VIP were capable of displacing the other from these binding sites. We propose that the hypotensive effect is via the same receptor type.