The recently discovered orexigenic peptide ghrelin is produced primarily by the stomach and circulates in blood at levels that increase during prolonged fasting in rats. When administered to rodents at supraphysiological doses, ghrelin activates hypothalamic neuropeptide Y/agouti gene-related protein neurons and increases food intake and body weight. These findings suggest that ghrelin may participate in meal initiation. As a first step to investigate this hypothesis, we sought to determine whether circulating ghrelin levels are elevated before the consumption of individual meals in humans. Ghrelin, insulin, and leptin were measured by radioimmunoassay in plasma samples drawn 38 times throughout a 24-h period in 10 healthy subjects provided meals on a fixed schedule. Plasma ghrelin levels increased nearly twofold immediately before each meal and fell to trough levels within 1 h after eating, a pattern reciprocal to that of insulin. Intermeal ghrelin levels displayed a diurnal rhythm that was exactly in phase with that of leptin, with both hormones rising throughout the day to a zenith at 0100, then falling overnight to a nadir at 0900. Ghrelin levels sampled during the troughs before and after breakfast correlated strongly with 24-h integrated area under the curve values (r = 0.873 and 0.954, respectively), suggesting that these convenient, single measurements might serve as surrogates for 24-h profiles to estimate overall ghrelin levels. Circulating ghrelin also correlated positively with age (r = 0.701). The clear preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans.

https://diabetes.diabetesjournals.org/content/diabetes/50/8/1714.full.pdf

A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans

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 ghr...

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Ghrelin enhances appetite and increases food intake in humans.

Background Weight loss causes changes in appetite and energy expenditure that promote weight regain. Ghrelin is a hormone that increases food intake in rodents and humans. If circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily by the stomach, weight loss after gastric bypass surgery may be accompanied by impaired ghrelin secretion. Methods We determined the 24-hour plasma ghrelin profiles, body composition, insulin levels, leptin levels, and insulin sensitivity in 13 obese subjects before and after a six-month dietary program for weight loss. The 24-hour ghrelin profiles were also determined in 5 subjects who had lost weight after gastric bypass and 10 normal-weight controls; 5 of the 13 obese subjects who participated in the dietary program were matched to the subjects in the gastric-bypass group and served as obese controls. Results Plasma ghrelin levels rose sharply shortly before and fell shortly after eve...

Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery

Ghrelin is a novel endogenous natural ligand for the growth hormone (GH) secretagogue receptor that has recently been isolated from the rat stomach. Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents. To investigate the possible involvement of ghrelin in the pathogenesis of human obesity, we measured body composition (by dual X-ray absorption) as well as fasting plasma ghrelin concentrations (radioimmunoassay) in 15 Caucasians (8 men and 7 women, 31 ± 9 years of age, 92 ± 24 kg body wt, and 29±10% body fat, mean ± SD) and 15 Pima Indians (8 men and 7 women, 33 ± 5 years of age, 97 ± 29 kg body wt, and 30 ± 8% body fat). Fasting plasma ghrelin was negatively correlated with percent body fat ( r = –0.45; P = 0.01), fasting insulin ( r = – 0.45; P = 0.01) and leptin ( r = –0.38; P = 0.03) concentrations. Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians ( P P

https://diabetes.diabetesjournals.org/content/diabetes/50/4/707.full.pdf

Circulating Ghrelin Levels Are Decreased in Human Obesity

The Distribution and Mechanism of Action of Ghrelin in the CNS Demonstrates a Novel Hypothalamic Circuit Regulating Energy Homeostasis

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (ICV) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after ICV administration was sustained for 24 hours. Following ICV administration of 3nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both ICV and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following ICV administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

The Novel Hypothalamic Peptide Ghrelin Stimulates Food Intake and Growth Hormone Secretion

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

The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.

Objective: Cocaine- and amphetamine-regulated transcript (CART) codes for a hypothalamic neuropeptide, CART (55–102), which inhibits food intake. Intracerebroventricular injection of CART (55–102) reduces appetite, but also results in motor abnormalities. More recently, studies have demonstrated that administration of CART directly into the paraventricular nucleus (PVN) increases food intake. To investigate the role of CART in the regulation of energy balance in the PVN, we used recombinant adeno-associated virus (rAAV) to overexpress CART in the PVN.



Methods and Procedures: Male Wistar rats were injected with either rAAV-encoding CART (rAAV-CART) or rAAV-encoding enhanced green fluorescent protein (rAAV-EGFP) as a control. Food intake and body weight were measured regularly. Animals were fed on normal-chow diet for the first 93 days of the study. After this point, they were fed on high-fat diet. Animals were killed 138 days postinjection and blood and tissues were collected for analysis.



Results: Overexpression of CART in the PVN resulted in increased cumulative food intake and body weight gain compared with rAAV-EGFP controls when fed normal chow. These changes became significant at day 65 and 79, respectively and were accentuated on a high-fat diet. A 4% increase in food intake was observed in rAAV-CART animals on a normal-chow diet and a 6% increase when fed a high-fat diet. At the end of the study, rAAV-CART-treated animals had higher circulating leptin concentrations in accord with their higher body weight.



Discussion: These data provide further evidence that hypothalamic CART plays an orexigenic role.

Overexpression of CART in the PVN Increases Food Intake and Weight Gain in Rats

Tuberoinfundibular peptide is a recently discovered agonist for the PTH receptor-2; the latter has a wide distribution including the external zone of the median eminence of the hypothalamus, suggesting a role in neuroendocrine function. We have investigated the effects of tuberoinfundibular peptide on the hypothalamo-pituitary axes in vitro and in vivo. Tuberoinfundibular peptide had effects on the hypothalamo-pituitary-adrenal axis with increased release of ACTH-releasing factor (tuberoinfundibular peptide 100 nm 4.4 ± 0.6 pmol/explant vs. control 2.9 ± 0.4 pmol/explant, P < 0.001) and increased release of arginine vasopressin (tuberoinfundibular peptide 100 nm 563.5 ± 55.5 fmol/explant vs. control 73.4 ± 9.6 fmol/explant, P < 0.01) from in vitro hypothalamic explants. Intracerebroventricular administration of tuberoinfundibular peptide and PTH(1–34) resulted in elevated plasma ACTH at 10 min post injection (saline 13.5 ± 2.1 pg/ml, tuberoinfundibular peptide 3 nmol 32.3 ± 4.0 pg/ml; P < 0.01 to saline: ...

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Helen L. Ward

Papers

The Novel Hypothalamic Peptide Ghrelin Stimulates Food Intake and Growth Hormone Secretion

The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.

Overexpression of CART in the PVN Increases Food Intake and Weight Gain in Rats

The Actions of Tuberoinfundibular Peptide on the Hypothalamo-Pituitary Axes