What can anorexia nervosa teach us about appetite regulation

With the increasing prevalence of obesity and its sequelae around the world, the regulation of appetite has continued to attract a high degree of attention—though largely without pharmacological means of inhibiting hunger on a long-term basis [1]. On the other side of the spectrum, however, are two disease states that result in a dangerous loss of body mass associated with increased mortality. The first of these conditions is disease-associated cachexia, a complex set of processes that involves an increase in metabolic rate, catabolism of lean and fat mass and—at a time when nutrients are direly needed—a paradoxical loss of appetite [2]. Cachexia is associated with a wide variety of underlying chronic diseases, including cancer, chronic heart failure, chronic kidney disease and chronic obstructive pulmonary disease. The very presence of cachexia in these diseases is associated with an increase in mortality. This has raised optimism that successful treatment of cachexia may help improve prognosis for affected patients. The second condition associated with dangerous loss of body mass is anorexia nervosa (AN). Individuals with AN avoid calorie intake and may go to great lengths to expend energy in a focused effort to achieve a pathologically thin body habitus [3]. As opposed to the increase in energy expenditure seen in cachexia, patients with AN exhibit a sharp decrease in resting energy expenditure, as their body attempts to conserve its remaining calories [4]. In this way, AN resembles starvation from food scarcity much more than it resembles cachexia. However, AN stands in sharp contrast to starvation in the stated appetite of those affected by it. Perception of appetite is a subjective process. Even in a state of fasting, patients with AN report far less desire to eat compared to healthy control subjects when shown images of energy-dense food [5]. Nevertheless, traditional appetite-regulating centers appear to be up-regulated in the setting of AN. This includes increases in the appetite-stimulating hormone ghrelin, with high levels of ghrelin found among AN patients [6]. These altered levels of ghrelin in AN include elevations in both acyl (i.e., active, orexigenic) and desacyl (in some settings anorexigenic [7]) ghrelin—as is also seen in patients with cachexia [8]. In animal models of cachexia, these physiologic increases in ghrelin fail to inhibit the anorexic output of the central melanocortin system in the hypothalamus [9,10]. Administration of supraphysiologic doses of ghrelin in animals and humans with cachexia results in an increase in food intake and body weight [9–12]. In this way, the syndrome of cachexia appears to confer resistance to ghrelin’s actions at baseline but is responsive to ghrelin as a treatment. Again, AN stands in contrast to cachexia on this front. It is presumed that patients with AN have a decrease in anorectic output of the melanocortin system (i.e., net appetite stimulation) but persist in food avoidance even during administration of pharmacological doses of ghrelin [13]. This is to say that the mechanics of ghrelin activity are likely to be functional but the ultimate output of food seeking behavior remains diminished. This phenomenon has been labeled “functional ghrelin resistance” [14]. Unfortunately, this resistance to food intake appears to be volitional in nature—or at least it is related to higher brain function, fueled by a distorted ideal body image [3]. In many ways patients with anorexia seem to have found a way to over-ride our powerful appetite stimulation pathways. In an unhealthy manner they have overcome society’s changes that have resulted in overweight or obesity in the majority of the US population. Nevertheless, there are likely ways in which AN can teach us about appetite regulation pathways. As discussed in this edition of Nutrition, there appear to be antibody-mediated adaptations of ghrelin activity. Terashi et al. investigated for levels of auto-antibodies (autoAbs) to acyl and desacyl ghrelin among control patients and among AN patients before and after refeeding [15]. In AN patients, the authors describe the presence of immune complexes of these autoAbs with desacyl ghrelin. These immune complexes sequester ghrelin autoAbs, resulting in lower levels of free ghrelin autoAbs at the same time as there are higher levels of free acyl ghrelin. The authors point out a potentially analogous situation in which autoAbs to insulin have been postulated to play a role in the shifts of bioavailable levels of insulin, with possible effects on hypoglycemia [16,17]. The physiological relevance of ghrelin autoAbs and immune complexes of these autoAbs with ghrelin remains unclear, but their presence in AN is an excellent starting point that can lead to investigation in the more medically complex cases involving elevation of ghrelin levels. While these ghrelin autoAbs had previously been demonstrated in control patients [18], investigation of ghrelin autoAbs may prove more difficult to assess in the setting of cachexia. In cachexia, there is a heterogeneity of comorbid medical conditions including the presence of systemic inflammation, which may modulate immune responses [19]. In the case of cancer cachexia it is not uncommon for tumor cells to secrete ghrelin, potentially further stimulating an increase in the production of autoAbs [20]. Similarly, testing levels of autoAbs in the course of cancer treatment may make it difficult to judge the effects of refeeding treatment vs. targeted chemotherapy. It will be important to evaluate for potential significance of ghrelin autoAbs in the setting of cachexia, but these added challenges will require careful consideration. Thus, through disregarding the usual appetite signals, patients with AN provide a more controlled look at the physiology of orexigenic signaling during periods of caloric deficit. This is not to minimize the serious nature of AN, which requires careful treatment regarding refeeding, monitoring for sequelae and psychological counseling. Nevertheless, patients with AN bear important physiological properties related to chronic starvation. In resisting society’s increase in food intake, patients with AN may teach us about the extremes of ghrelin resistance in the process.