ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.

Ghrelin is a recently identified endogenous ligand for the growth hormone secretagogue receptor. It is synthesized predominantly in the stomach and found in the circulation of healthy humans. Ghrelin has been shown to promote increased food intake, weight gain and adiposity in rodents. The effect of ghrelin on appetite and food intake in man has not been determined. We investigated the effects of intravenous ghrelin (5.0 pmol/kg/min) or saline infusion on appetite and food intake in a randomised double-blind cross-over study in nine healthy volunteers. There was a clear-cut increase in energy consumed by every individual from a free-choice buffet (mean increase 28 ± 3.9%, p<0.001) during ghrelin compared with saline infusion. Visual analogue scores for appetite were greater during ghrelin compared to saline infusion. Ghrelin had no effect on gastric emptying as assessed by the paracetamol absorption test. Ghrelin is the first circulating hormone demonstrated to stimulate food intake in man. Endogenous ghrelin is a potentially important new regulator of the complex systems controlling food intake and body weight. _____________________________________________________________________________________________________

Ghrelin, a circulating growth hormone-releasing peptide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghrelin concentration was compared with that during fasting. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 ؎ 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 ؎ 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimulated food intake most markedly in the arcuate nucleus (Arc) (0 -1 h food intake, 427 ؎ 43% of control; P < 0.001 vs. control, P < 0.01 vs. all other nuclei), which is potentially accessible to the circulation. After chronic systemic or intracerebroventricular (ICV) administration of ghrelin for 7 days, cumulative food intake was increased (intraperitoneal ghrelin 13.6 ؎ 3.4 g greater than saline-treated, P < 0.01; ICV ghrelin 19.6 ؎ 5.5 g greater than saline-treated, P < 0.05). This was associated with excess weight gain (intraperitoneal ghrelin 21.7 ؎ 1.4 g vs. saline 10.6 ؎ 1.9 g, P < 0.001; ICV ghrelin 15.3 ؎ 4.3 g vs. saline 2.2 ؎ 3.8 g, P < 0.05) and adiposity. These data provide evidence that ghrelin is important in long-term control of food intake and body weight and that circulating ghrelin at fasting concentrations may stimulate food intake.

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...