Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.     

Gastrointestinal targets of appetite regulation in humans

The aim of this paper is to describe and discuss relevant aspects of the assessment of physiological functions – and related biomarkers – implicated in the regulation of appetite in humans. A short introduction provides the background and the present state of biomarker research as related to satiety and appetite. The main focus of the paper is on the gastrointestinal tract and its functions and biomarkers related to appetite for which sufficient data are available in human studies. The first section describes how gastric emptying, stomach distension and gut motility influence appetite; the second part describes how selected gastrointestinal peptides are involved in the control of satiety and appetite (ghrelin, cholecystokinin, glucagon‐like peptide, peptide tyrosin‐tyrosin) and can be used as potential biomarkers. For both sections, methodological aspects (adequacy, accuracy and limitation of the methods) are described. The last section focuses on new developments in techniques and methods for the assessment of physiological targets involved in appetite regulation (including brain imaging, interesting new experimental approaches, targets and markers). The conclusion estimates the relevance of selected biomarkers as representative markers of appetite regulation, in view of the current state of the art.     

Effect of fat emulsion (Fabuless) on orocecal transit time in healthy men

Background. Given the growing prevalence of overweight and related health consequences, there is increased interest in the search for novel dietary strategies for weight control. A food ingredient, an emulsion based on palm and oat oil (Fabuless, previously known as Olibra), has been associated with short-term reductions of food intake, induction of satiety, alternation in the satiety hormones, as well as long-term effects on weight control. The mechanism by which it can exert these effects is so far unclear, though it has been suggested that the “ileal break” may play a role in increasing gastrointestinal transit time. The aim of this study was to investigate the effects of this stable fat emulsion on orocecal transit time in healthy men. Material and methods. In a controlled, double-blind, cross-over-designed study, 15 healthy men (aged 20–59 years, body mass index (BMI) 22–28), randomly allocated to two treatments, consumed the stable fat emulsion or a milk fat in yoghurt during two days of investigation, with an interval of 1 week. Orocecal transit time was determined by following blood sulfapyridine levels, which is a metabolite of salazopyrine in the colon. Results. A statistically significant delay in the appearance of sulfapyridine in serum was obtained after active treatment versus control treatment, corresponding to a 45-min longer orocecal transit time due to fat emulsion consumption. Conclusions. This study provides the first evidence to suggest that this stable fat emulsion may affect the ileal brake mechanism by slowing down the gastrointestinal transit time, which might explain the weight control and appetite suppression previously observed in association with this emulsion.     

Effects of cues associated with meal interruption on feeding behavior

Food consumption is controlled by both internal and external factors. Environmental signals associated with food may prepare an animal to forage, consume and digest more effectively. Furthermore, environmental cues that provide information about food availability enable animals to make predictions about future food resources and act upon that knowledge in appropriate fashion. For example, when exposed to a cue that signals the presence of food, animals can eat beyond their present needs to cope with predicted future famine. Interestingly, cues previously paired with meal interruption have a similar effect. In two experiments, food-deprived rats learned to associate one conditioned stimulus (CS+) with delivery of a food unconditioned stimulus (US), and another stimulus (IS) with an unexpected termination of CS-US trials. Subsequently, both CS+ and IS enhanced consumption of the US food by sated rats. The results of Experiment 2 indicated that IS's ability to potentiate feeding of sated rats in test depended more on its accompanying CS+ termination in training than on its signaling reductions in US frequency. These experiments may provide a novel animal model of binge-like behaviors in sated rats induced by external cues paired with meal interruption.     

Sex-based differences in the behavioral and neuronal responses to food

Sex-based differences in food intake related behaviors have been observed previously. The objective of this study was to examine sex-based differences in the behavioral and neuronal responses to food. 22 women and 21 men were studied. After 6 days of controlled eucaloric feeding, ad libitum energy intake (EI) was measured for 3 days. Appetite ratings using visual analog scales were obtained before and after each meal. Functional magnetic resonance imaging was performed in the overnight fasted state on the last day of eucaloric feeding while subjects were presented visual stimuli of food and neutral non-food objects. While hunger and prospective consumption were not different between sexes, women had higher post-meal satiety ratings and dietary restraint than men. Images of hedonic foods resulted in significantly greater activation of lateral and dorsolateral prefrontal cortex (DLPFC) and parietal cortex in women as compared to men. No brain regions were more activated in men as compared to women. Men increased their EI during the ad libitum diet phase. While measures of appetite or feeding behaviors did not correlate with either neuronal activation or subsequent EI, DLPFC activation in response to hedonic foods was negatively correlated with EI. In summary, greater prefrontal neuronal responses to food cues in women may suggest increased cognitive processing related to executive function, such as planning, guidance or evaluation of behavior. Finally, increased DLPFC activation, perhaps relating to inhibitory cognitive control in response to food cues may be a better predictor of food intake than behavioral measures.     

Effects of chronic fenfluramine administration on hypothalamic neuropeptide mRNA expression

Appetite suppressants lose efficacy when given chronically; the mechanisms are unknown. We gave male rats once-daily dl-fenfluramine (dl-FEN, 5 mg/kg, i.p.) injections for 15 days and measured mRNA expression of corticotropin releasing factor (CRF), neuropeptide Y (NPY) and proopiomelanocortin (POMC) in hypothalamic neurons on days 1, 2 and 15. dl-FEN decreased food intake on days 1-2 but not on day 15. The drug increased CRF mRNA and decreased NPY mRNA on days 1-2; on day 15, NPY mRNA was normal, but CRF mRNA remained elevated. No changes occurred in POMC mRNA. Thus, only the NPY mRNA response to dl-FEN correlated with changes in food intake over time in a manner consistent with the known effects of NPY on food intake.