The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

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

Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it "ghrelin," after a word root ("ghre") in Proto-Indo-European languages meaning "grow." Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2004

Ghrelin: Structure and Function

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...

Alison M. Wren

Papers

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Putative auto-infarct of a pancreatic gastrinoma: a case report.