Alison M. Wren

Gut hormone PYY3-36 physiologically inhibits food intake

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.

Ghrelin increases food intake in obese as well as lean subjects

OBJECTIVE:To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin.DESIGN:Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min.SUBJECTS:In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5±0.17 kg/m2) and 12 healthy overweight and obese subjects (mean BMI 31.9±1.02 kg/m2).MEASUREMENTS:Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone.RESULTS:Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6±9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1±10.6% in the lean and 70.1±15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group.CONCLUSION:Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.

The Hypothalamic Mechanisms of the Hypophysiotropic Action of Ghrelin

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor, expressed in the hypothalamus and pituitary. Ghrelin, like synthetic GHSs, stimulates food intake and growth hormone (GH) release following systemic or intracerebroventricular administration. In addition to GH stimulation, ghrelin and synthetic GHSs are reported to stimulate the hypothalamo-pituitary-adrenal (HPA) axis in vivo. The aims of this study were to elucidate the hypothalamic mechanisms of the hypophysiotropic actions of ghrelin in vitro and to assess the relative contribution of hypothalamic and systemic actions of ghrelin on the HPA axis in vivo. Ghrelin (100 and 1,000 nM) stimulated significant release of GH-releasing hormone (GHRH) from hypothalamic explants (100 nM: 39.4 ± 8.3 vs. basal 18.3 ± 3.5 fmol/explant, n = 49, p < 0.05) but did not affect either basal or 28 mM KCl-stimulated somatostatin release. Ghrelin (10, 100 and 1,000 nM) stimulated the release of both corticotropin-releasing hormone (CRH) (100 nM: 6.0 ± 0.8 vs. basal 4.2 ± 0.5 pmol/explant, n = 49, p < 0.05) and arginine vasopressin (AVP) (100 nM: 49.2 ± 5.9 vs. basal 35.0 ± 3.3 fmol/explant, n = 48, p < 0.05), whilst ghrelin (100 and 1,000 nM) also stimulated the release of neuropeptide Y (NPY) (100 nM: 111.4 ± 25.0 vs. basal 54.4 ± 9.0 fmol/explant, n = 26, p < 0.05) from hypothalamic explants in vitro. The HPA axis was stimulated in vivo following acute intracerebroventricular administration of ghrelin 2 nmol [adrenocorticotropic hormone (ACTH) 38.2 ± 3.9 vs. saline 18.2 ± 2.0 pg/ml, p < 0.01; corticosterone 310.1 ± 32.8 ng/ml vs. saline 167.4 ± 40.7 ng/ml, p < 0.05], but not following intraperitoneal administration of ghrelin 30 nmol, suggesting a hypothalamic site of action. These data suggest that the mechanisms of GH and ACTH regulation by ghrelin may include hypothalamic release of GHRH, CRH, AVP and NPY.

Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment

Malnutrition is a common complication in patients on dialysis and is strongly associated with poor prognosis. Effective therapy could substantially improve morbidity and mortality, but neither enteral nor parenteral supplementation provide long-term benefit because of the strong appetite suppression seen in such patients. We performed a double-blinded randomized crossover study of a week-long treatment with daily subcutaneous ghrelin, a gut hormone that regulates hunger through the hypothalamus, in a group of 12 malnourished dialysis patients. Ghrelin administration increased ghrelin levels in circulation, modestly reduced blood pressure for up to 2 h, and immediately and significantly increased appetite, with an increase in energy intake noted at the first study meal. Persistence of this effect throughout the week was confirmed with food diaries and final study meals. Energy expenditure, measured with free-living pulse and motion monitors, was unchanged by ghrelin. Our study shows that daily treatment with ghrelin achieves a sustained positive change in energy balance in malnourished dialysis patients. Direct manipulation of appetite with ghrelin or its analogs represents an attractive and promising therapeutic strategy for this difficult clinical problem.

PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.

OBJECTIVE Peptide YY3–36 (PYY3–36), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3–36 and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3–36 or oxyntomodulin or combined PYY3–36/oxyntomodulin. RESULTS Energy intake during coadministration of PYY3–36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS The anorectic effects of PYY3–36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Gut Hormones as Potential New Targets for Appetite Regulation and the Treatment of Obesity

Food intake and bodyweight are tightly regulated by the brainstem, hypothalamus and reward circuits. These centres integrate diverse cognitive inputs with humoral and neuronal signals of nutritional status. Our knowledge of the role of gut hormones in this complex homeostatic system has expanded enormously in recent years. This review discusses both the role of gut hormones in appetite regulation, and the current state of development of gut hormone-based obesity therapies, with a particular focus on pancreatic polypeptide, peptide YY, amylin, glucagon-like peptide-1, oxyntomodulin, cholecystokinin and ghrelin. Several gut hormone-based treatments for obesity are under investigation in phase II and III clinical trials, and many more are in the pipeline.

Physiology: Does gut hormone PYY3|[ndash]|36 decrease food intake in rodents? (reply)

The results of Tschöp et al. on the lack of effect of peripheral administration of PYY3–36 on food intake in rodents are at odds with both the published literature (our Table 1) and with earlier data generated by the Tschöp laboratory.

How appetite is controlled

It is now recognized that appropriate regulation of energy intake and energy expenditure, and thus maintenance of body weight, relies on complex hypothalamic neurocircuitry. The importance of key neuropeptide systems identified in rodents is now being established in humans. Notably, mutations in the melanocortin MC4 receptor are found in as many as 4% of the morbidly obese. Intranasal administration of a melanocortin fragment known to activate the MC4 receptor decreases adiposity in humans. Since the discovery of leptin, attention has also focused on peripheral signals that regulate food intake and energy expenditure either directly or via feedback on hypothalamic circuits. Notable new discoveries in this area include the gastric hormone ghrelin and circulating melanocortins.