Original ArticlesLeptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients
Introduction
Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders of unknown etiology that are characterized by aberrant patterns of feeding behavior and weight regulation. In addition, there are disturbances in attitudes toward weight and shape and the perception of body shape. In AN there is an inexplicable fear of weight gain and unrelenting obsession with fatness even in the face of increasing cachexia. BN usually emerges after a period of dieting, which may or may not have been associated with weight loss. In BN, binge eating is usually followed by either self-induced vomiting, or by some other means of compensation for the excess of food ingested. The majority of people with BN have irregular feeding patterns, and satiety may be impaired. Although abnormally low body weight is an exclusion for the diagnosis of BN, some 25–30% of bulimics presenting to treatment centers have a prior history of AN; however, all bulimics have pathological concern with weight and shape. Common to both individuals with AN and BN are low self-esteem, depression, and anxiety. In the past decade, a number of neuropeptides have been discovered that have profound effects upon appetite and weight regulation. These include neuropeptide Y (NPY), peptide YY (PYY), and leptin. It is theoretically possible that alternations in the activity of these brain peptides could contribute to the pathophysiology of AN or BN.
Leptin is the hormone product of the mouse ob gene and human homologue gene, LEP (Zhang et al 1994). It is secreted predominantly by adipose tissue cells, and it is thought to contribute to the regulation of body fat (Considine et al 1996). Leptin may decrease food intake and reduce body weight by decreasing NPY synthesis or by inhibiting NPY’s action as an appetite stimulant (Stephens et al 1995), increasing metabolic rate by activation of β-adrenergic receptors, and possibly by having its own, or other peptide-mediated anorexigenic properties (Erikson et al 1996). In addition to its role in body weight regulation, it has become apparent that leptin may also be a metabolic signal that mediates impaired reproductive ability in conditions of extreme over- and underweight Chehab 1996, Chehab et al 1996, Kopp et al 1997.
People with AN who are underweight and malnourished have consistently been found to have significantly reduced plasma and cerebrospinal fluid (CSF) leptin concentrations compared to normal weight control subjects Hebebrand et al 1995, Grinspoon et al 1996, Baranowska et al 1997, Ferron et al 1997, Mantzoros et al 1997a. Reduced leptin concentrations are probably a normal physiological response to starvation in anorexia nervosa. Interestingly, people with AN have an increase in plasma leptin levels during refeeding and weight gain. Moreover, leptin concentrations may reach normal values before full weight restoration Hebebrand et al 1997, Mantzoros et al 1997a, suggesting that premature normalization of leptin concentrations might contribute to difficulty in achieving and sustaining a normal weight in anorexia nervosa. Less work has examined the leptin status of individuals with bulimia nervosa; however, it appears that serum leptin concentrations in ill bulimics are similar to those of normal control women and are correlated with body mass Argente et al 1997, Ferron et al 1997, Kopp et al 1997, Zipfel et al 1998.
NPY and PYY are related 36-amino-acid peptides that are potent activators of feeding behavior. Our group (Kaye et al 1990) found that underweight anorexia nervosa patients had significantly elevated concentrations of CSF NPY compared to healthy volunteers; however, CSF NPY concentrations normalized after long-term recovery. In contrast patients with anorexia nervosa, whether underweight or recovered, had normal CSF PYY concentrations.
The powerful permissive effect (without the development of tolerance) that central PYY administration has on food ingestion has led to speculation that increased activity of PYY may contribute to bulimia nervosa Morley et al 1985, Morley and Blundell 1988. CSF PYY values for normal weight bulimic women studied when bingeing and vomiting are similar to control subjects (Kaye et al 1990). In contrast, CSF PYY concentrations were significantly elevated in bulimic women studied after a month of abstinence from bingeing and vomiting compared to healthy volunteer women and patients with anorexia nervosa. This CSF PYY finding has been confirmed in a new and larger group of normal weight bulimic women (M. Lesem, personal communication). In contrast to women with anorexia nervosa, patients with bulimia nervosa were found to have normal CSF NPY levels.
Investigating the etiological role of neuropeptides in women who are ill with eating disorders is problematic, since the compromised nutritional status of these individuals may independently affect neuropeptides levels. Identification and assessment of individuals before the onset of the eating disorder would overcome the influences of impaired nutrition status, but such studies are prohibitive given the low prevalence rates and our current inability to accurately predict future sufferers of eating disorders. One way of determining whether a neuropeptide contributes to etiology of an eating disorder is to determine its status after long-term recovery. Abnormalities in a neurochemical after long-term recovery may indicate a trait-related, rather than state-related, disturbance. To determine the possibility of trait-related neuropeptide disturbances in women with eating disorders, the present study measured plasma leptin and CSF leptin, NPY, and PYY in individuals who were long-term recovered from an eating disorder in comparison to normal control women.
Section snippets
Participants
Women who had previously, in their lifetime, met DSM-III-R criteria for bulimia nervosa (RNWB), anorexia nervosa with bulimia (RBAN), and restricting anorexia nervosa (RRAN) were recruited for this study. Subjects had been previously treated in the eating disorders treatment program at Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania or were recruited through advertisements. DSM-III-R eating disorder diagnoses were arrived at by clinical interview with a psychiatrist (WHK). To
Participant characteristics
The characteristics of all participants and of the subset of participants who agreed to take part in the LP are presented in Table 1. Although the mean ages of all groups were in the 20s, the RNWB group was significantly older than the other groups (Table 1). The RRAN women had a significantly lower body mass index (kg/m2) than the NC and RNWB groups. The percent ideal weight of the RRAN women was significantly lower, and the percent ideal current weight of the RNWB women was significantly
Discussion
NPY, PYY, and leptin concentrations are normal in women who recover from AN and BN. These data suggest that alterations of these peptides found in ill AN and BN are likely to be secondary to malnutrition and are not traits that cause AN or BN. We replicated our initial finding of normal CSF NPY after long-term recovery from AN (Kaye et al 1990). Although PYY concentrations have been found to increase after short-term abstinence from bingeing and vomiting in BN (Kaye et al 1990), the present
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