Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

UMR INSERM 837, Development and Plasticity of Postnatal Brain Lille, France.
Frontiers in Endocrinology 02/2013; 4:15. DOI: 10.3389/fendo.2013.00015
Source: PubMed


Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.

Download full-text


Available from: Suzanne L Dickson, Sep 18, 2014
1 Follower
82 Reads
  • Source
    • "The meal pattern of AN patients is characterized by low interest in obtaining food, and by smaller meals (Heaner and Walsh, 2013), indicating alteration of both hunger and satiation mechanisms. Accordingly, ghrelin, a 28 amino acid peptide hormone (Kojima et al., 1999), attracted significant attention for its possible implication in the pathophysiology of AN (Méquinion et al., 2013; Zhang et al., 2012) due to its properties to induce hunger by activating central orexigenic pathways such as hypothalamic neuropeptide Y (NPY) neurons (Holzer et al., 2012; Wu et al., 2012). Ghrelin is derived from a 117 amino acid polypeptide precursor, the preproghrelin, expressed in gastric mucosa (Date et al., 2000). "
    [Show abstract] [Hide abstract]
    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.
    Neuropeptides 04/2015; 51. DOI:10.1016/j.npep.2015.04.003 · 2.64 Impact Factor
  • Source
    • "The severity of the medical consequences is also linked to the duration of illness [8]. In particular, AN is associated with a nutritionally acquired resistance to growth hormone (GH), low leptinemia, high levels of adiponectin and cortisol, hypothalamic amenorrhea, osteopenia, and osteoporosis (reviewed in Méquinion et al [9]). At least some of these alterations are believed to be adaptive responses necessary to survive the severe and long-term caloric restriction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment.
    PLoS ONE 08/2014; 9(8):e103775. DOI:10.1371/journal.pone.0103775 · 3.23 Impact Factor
  • Source
    • "As reviewed by Mequinion et al. (2013), several routes exist through which peripheral ghrelin may cross the blood–brain barrier to act centrally, and though the integrity of these routes has not been examined in the context of starvation, even if disrupted, this would not explain the absence of or disparate Fig. 2. Regions demonstrating significant relationships between serum fasting acylated ghrelin and BOLD response to food (vs. objects): (A) Positive relationships between ghrelin and high-calorie vs. object BOLD activity in healthy-weight control subjects in the right amygdala (A1), right hippocampus (A2) right anterior insula (A3), and right OFC (A4); (B) Negative relationship between ghrelin and high-calorie vs. object BOLD activity in AN-WR women in the left hippocampus; (C) Positive relationship between ghrelin and low-calorie vs. object BOLD activity in AN women in the right OFC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evidence contributing to the understanding of neurobiological mechanisms underlying appetite dysregulation in anorexia nervosa draws heavily on separate lines of research into neuroendocrine and neural circuitry functioning. In particular, studies consistently cite elevated ghrelin and abnormal activation patterns in homeostatic (hypothalamus) and hedonic (striatum, amygdala, insula) regions governing appetite. The current preliminary study examined the interaction of these systems, based on research demonstrating associations between circulating ghrelin levels and activity in these regions in healthy individuals. In a cross-sectional design, we studied 13 women with active anorexia nervosa (AN), 9 women weight-recovered from AN (AN-WR), and 12 healthy-weight control women using a food cue functional magnetic resonance imaging paradigm, with assessment of fasting levels of acylated ghrelin. Healthy-weight control women exhibited significant positive associations between fasting acylated ghrelin and activity in the right amygdala, hippocampus, insula, and orbitofrontal cortex in response to high-calorie foods, associations which were absent in the AN and AN-WR groups. Women with AN-WR demonstrated a negative relationship between ghrelin and activity in the left hippocampus in response to high-calorie foods, while women with AN showed a positive association between ghrelin and activity in the right orbitofrontal cortex in response to low-calorie foods. Findings suggest a breakdown in the interaction between ghrelin signaling and neural activity in relation to reward responsivity in AN, a phenomenon that may be further characterized using pharmacogenetic studies.
    Psychiatry Research: Neuroimaging 05/2014; 223(2). DOI:10.1016/j.pscychresns.2014.04.015 · 2.42 Impact Factor
Show more