Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

Abstract

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.

Glucose metabolism alterations in patients with bipolar disorder

“…Ghrelin can cross the blood-brain barrier and act bidirectionally in the periphery and in the brain. In addition to its well-known role as a regulator of energy balance and food intake, Ghrelin may be involved in several brain mechanisms (Méquinion et al, 2013), many of those are altered in mood disorders as circadian rhythms (Kluge et al, 2013) and neuroinflammation (Miyake and Yamamura, 2009;Beynon et al, 2013). All these evidences indicated that an imbalance in Glucagon, GLP-1, GIP and Ghrelin levels might play a role in the pathogenesis of BD and in the mechanism causing the comorbidity between mood and metabolic disorders (Czepielewski et al, 2013).…”

Ghrelin and Obesity: Identifying Gaps and Dispelling Myths. A Reappraisal

“…Insight into the modification of the endogenous ghrelin system seems to be promising not only for the control of obesity, but also for the management of clinically significant anorexia and pathological weight reduction. Accumulating evidence has shown that in patients with anorexia nervosa, there is a paradoxical increase in plasma ghrelin level even when compared with matched controls or obese patients (26), suggesting that there might be an insensitivity to ghrelin (27). Moreover, in vitro studies have documented that intra-peritoneal or systemic administration of ghrelin has the potential to improve the appetite and the nutritional status, and at the same time reduce the metabolic rate in patients with end-stage cancer (5).…”

Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa

“…Among the neuroendocrine systems controlling human appetite, studies of active AN have consistently implicated elevated ghrelin in the pathophysiology of abnormal appetite in this disorder (e.g., see Prince et al, 2009; Ogiso et al, 2011; Yi et al, 2011; Mequinion et al, 2013). Ghrelin is a potent orexigenic peptide, with levels rising sharply just before meals and falling to nadir within an hour after eating (Cummings et al, 2001; Shiiya et al, 2002).…”