Acute and chronic suppression of the central ghrelin signaling reveals a role in food anticipatory activity

Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 4.37). 05/2011; 21(5):384-92. DOI: 10.1016/j.euroneuro.2010.06.005
Source: PubMed


Using the rodent activity-based anorexia (ABA) model that mimics clinical features of anorexia nervosa that include food restriction-induced hyperlocomotion, we found that plasma ghrelin levels are highly associated with food anticipatory behaviour, measured by running wheel activity in rats. Furthermore, we showed that ghrelin receptor (GHS-R1A) knockout mice do not anticipate food when exposed to the ABA model, unlike their wild type littermate controls. Likewise, food anticipatory activity in the ABA model was suppressed by a GHS-R1A antagonist administered either by acute central (ICV) injection to rats or by chronic peripheral treatment to mice. Interestingly, the GHS-R1A antagonist did not alter food intake in any of these models. Therefore, we hypothesize that suppression of the central ghrelin signaling system via GHS-R1A provides an interesting therapeutic target to treat hyperactivity in patients suffering from anorexia nervosa.

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Available from: Suzanne L Dickson, Oct 10, 2015
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    • "Animals with limited access to food learn to anticipate food availability by increasing locomotion (food anticipatory activity [FAA]) and optimize their consummatory behavior during that period. Ghrelin signaling is critical for FAA and consumption (Blum et al., 2009; Verhagen et al., 2011). When assessed on a chow diet, we found that the total locomotor activity by AgRP-ablated "
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    ABSTRACT: Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake-a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "Thus, in order to determine the main source of increased plasma ghrelin during starvation, the aim of this study was to analyze, using in situ hybridization, preproghrelin mRNA-expressing cells in the stomach and hypothalamus of mice with chronic malnutrition and body weight loss, including activity-based anorexia (ABA), a rodent model of AN (Carrera et al., 2001). Indeed, previous studies have shown that prolonged starvation in mice massively increases plasma ghrelin (Goldstein et al., 2011; Méquinion et al., 2015) and that a significant increase is also observed in the ABA model (Verhagen et al., 2011). "
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    ABSTRACT: Plasma levels of ghrelin, an orexigenic peptide, are increased during conditions of chronic starvation, such as in patients with anorexia nervosa. However, it is not known whether such increase can be related to the number of preproghrelin mRNA-expressing cells in the stomach, and if chronic starvation may activate a tentative central ghrelin production. In this work, in situ hybridization technique was used to analyze the presence and number of preproghrelin mRNA-expressing cells in the stomach and the hypothalamus of mice with activity-based anorexia (ABA) induced by the combination of running wheel activity with progressive, during 10 days, feeding-time restriction (FTR) and compared with sedentary FTR, ABA pair-fed (PF) and ad libitum-fed control mice. All food-restricted mice lost more than 20% of body weight. Body weight loss was similar in ABA and PF mice, but it was more pronounced than in FTR mice. Food intake was also lower in ABA than in FTR mice. Preproghrelin mRNA-expressing cells in the stomach were increased proportionally to the body weight loss in all food-restricted groups with the highest number in ABA mice. No preproghrelin mRNA-producing cells were detectable in the hypothalamus of either control or food-restricted mice. Thus, the increased number of gastric preproghrelin mRNA-producing cells during chronic starvation proportionally to the body weight loss and reduced food intake may underlie increased plasma ghrelin. Hyperactivity-induced anorexia appears to further increase the number of preproghrelin mRNA-producing cells in the stomach. No evidence was found for ghrelin expression in the hypothalamus, not even in any of the present experimental models. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "However, there is mixed evidence as to whether ghrelin can act a zeitgeber. Two studies show that ghrelin receptor knock out mice fail to anticipate a daily meal (LeSauter et al., 2009; Davis et al., 2011; Verhagen et al., 2011), however other studies have shown that ghrelin ligand or receptor knock-out mice do continue to show FAA (Blum et al., 2009; Szentirmai et al., 2010; Gunapala et al., 2011). Overall, the evidence suggests that ghrelin is not the unidentified " food-entrainable oscillator " but rather that it exerts effects on the circadian system by acting downstream from or in parallel with a food entrainable oscillator (Patton and Mistlberger, 2013). "
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