Opposite modifications in circulating leptin and soluble leptin receptor across the eating disorder spectrum.

Leptin is thought to modulate feeding behaviour, body weight and energy metabolism by acting through specific cellular receptors. Derangements of leptin production have been repeatedly reported in patients with anorexia nervosa (AN) or bulimia nervosa (BN), but no information has been provided on the functional status of leptin receptors in these disorders. Therefore, we measured plasma levels of leptin and its soluble receptor (Ob-Re) in a total of 130 women, including 22 patients with AN, 45 patients with BN, 18 patients with the binge-eating disorder (BED), 12 non-binge eating obese women and 33 healthy women. Circulating leptin was drastically reduced in underweight anorexics and normal-weight bulimics, but increased in overweight BED patients and non-binge-eating obese women. Conversely, plasma levels of Ob-Re were significantly increased in patients with AN or BN, but decreased in BED and non-binge-eating obese women. Significant inverse correlations were detected between plasma levels of leptin and those of Ob-Re in all the subject groups, except in non-binge-eating obese subjects. These results show, for the first time, that opposite modifications occur in circulating levels of leptin and Ob-Re across the eating-disorder spectrum. The relevance of these findings to the pathophysiology and treatment of eating disorders remains to be elucidated.

Aggressive behavioral characteristics and endogenous hormones in women with Bulimia nervosa.

Increased aggressiveness frequently occurs in patients with bulimia nervosa (BN), but its neurobiological correlates have been poorly investigated. In this study, we investigated possible relationships between such clinical measure and blood levels of endogenous hormones in patients with BN. Morning plasma levels of testosterone, 17beta-estradiol, prolactin (PRL) and cortisol were measured in 33 bulimic women and 22 healthy female controls. The eating-related psychopathology, depression and aggressiveness were rated by specific psychometric scales. Bulimic patients showed decreased plasma levels of PRL and 17beta-estradiol, and increased concentrations of cortisol and testosterone. Moreover, patients scored higher than healthy controls on rating scales assessing eating-related psychopathology, depressive symptoms and aggressiveness. A significant positive correlation was found between testosterone plasma levels and aggressiveness in patients but not in controls. These findings suggest that in BN, increased plasma levels of testosterone may play a role in the modulation of aggressiveness.

Plamsa leptin response to acute fasting and refeeding in untreated women with bulimia nervosa.

Leptin is known to regulate body weight, energy balance, and reproduction. Therefore, investigation of its physiology is of obvious interest in bulimia nervosa (BN), an eating disorder characterized by body weight-related psychopathology, acute changes in the energy balance, and reproductive alterations. To date, the few studies that have assessed leptin production in BN have had several limitations, including the measurement of blood leptin levels in treated patients and the lack of normal weight healthy controls, so that the information they provide is not conclusive. As the investigation of leptin dynamics is likely to be more informative, we decided to assess leptin response to acute fasting and refeeding in both untreated patients with BN and healthy controls. Twelve women meeting the diagnostic criteria for BN of the Diagnostic and Statistical Manual of Mental Disorders, and 10 healthy women of the same age range participated in a 3-day study. At 1800 h on day 1, they received a meal of 1088 Cal, with 53% carbohydrates, 17% protein, and 30% fat. Then, they fasted until 1800 h on day 2, when they received the same meal. On day 3, they received a standard hospital diet of 2600 Cal, divided into 3 meals, with the same percentages of nutrients as described above. Blood samples were collected at different time points for plasma leptin, glucose, and insulin measurements. In bulimic patients, plasma leptin values were significantly lower than in healthy women (P < 0.0001) and were positively related to body weight, expressed as body mass index (r = 0.86; P < 0.0001). The leptin response to the fasting/refeeding paradigm significantly differed between patients and controls (time x group interaction, P < 0.0001). In fact, in healthy subjects, acute fasting induced a 58% decline in the plasma leptin concentration, whereas such a decrease was only 7% in bulimic women (P < 0.001). After acute refeeding, plasma leptin increased in both groups, although in the patients it did not reach the absolute values observed in normal controls. No significant difference was observed between bulimics and controls in plasma insulin response to the fasting/refeeding paradigm, whereas an abnormal increase in blood glucose levels was observed in the patients after the first meal following acute fasting. We conclude that in untreated women with BN, leptin, despite its very low plasma values, still holds its function as a sensor of body weight changes, but loses its role of signaling acute changes in energy balance.

Seasonal variation in plasma prolactin response to D-fenfluramine in healthy subjects.

To assess dynamically a seasonal variation in the functioning of the central serotonin (5-HT) system, we investigated the prolactin (PRL) response to the specific serotonergic agent D-fenfluramine (D-FEN) in the different seasons of the year. Thirteen healthy women and 11 healthy men (six for each season), aged 20-50 years, received PO 30 mg D-FEN and placebo, according to a randomized double-blind design. As compared to placebo, D-FEN induced a clear-cut increase in plasma PRL levels in all the seasons; this response was higher in fall than in spring and summer (p < .01 and < .05, respectively). In all the subjects, as a group, the hormone response to the 5-HT probe was inversely correlated with the body weight and age. These results document a seasonal variability in the PRL response to D-FEN, which suggests a seasonal fluctuation in central 5-HT transmission in healthy humans.

Melatonin and cortisol secretion in patients with primary obsessive-compulsive disorder.

Plasma levels of melatonin and cortisol were measured over a 24-hour period in seven patients with primary obsessive-compulsive disorder (OCD) and seven matched healthy control subjects. In OCD patients, the 24-hour secretion of melatonin was reduced as compared with that in healthy control subjects, whereas its circadian rhythm was preserved. In addition, in OCD patients, the overall secretion of cortisol was higher than that in control subjects, but there was no change in the circadian pattern of cortisol secretion. No correlation was found between clinical parameters and hormone levels.

Physical stress in the middle of the dark phase does not affect light-depressed plasma melatonin levels in humans.

The human pineal gland has been shown to be unresponsive to stress-induced sympathetic activation during the day. However, the effects of stress on human melatonin production have received little investigation at night, when the pinealocytes should be physiologically responsive to noradrenergic stimulation. For this purpose, plasma melatonin and cortisol levels were measured in 7 healthy men (aged 25-34 years), both in resting condition and before and after a physical exercise performed between 23.40 and 24.00 h, 30 min after exposure to bright light (2,500 lx). The exercise consisted in bicycling on a bicycle ergometer at 50% of the personal maximum work capacity (MWC) for 10 min, followed by another 10 min of bicycling at 80% of the MWC. The results clearly showed that physical exercise does not affect light-depressed plasma melatonin levels, whereas it clearly increased plasma cortisol concentrations (p less than 0.002, two-way ANOVA with repeated measures), systolic blood pressure, pulse pressure and heart rate. These findings suggest that the human pineal gland is not responsive to systemic sympathetic activation induced by physical stress even in the middle of the dark phase.

Temporal relationship between melatonin and cortisol responses to nighttime physical stress in humans.

It has been shown that, in the rat, physical stress decreases pineal melatonin levels at night, whereas it increases melatonin production during the day. We have demonstrated that nighttime physical exercise is able to blunt the nocturnal surge of plasma melatonin in healthy subjects. Since this effect might be mediated by exercise-induced cortisol secretion from the adrenal gland, in the present investigation we studied the relationship between cortisol and melatonin responses to nighttime physical stress in six healthy men, aged 28-33 yr. The physical stress consisted of bicycling on a bicycle ergometer at 50% of personal maximum work capacity (MWC), followed by another 10 min of bicycling at 80% of MWC. According to our previous data, physical exercise performed between 2240 h and 2300 h significantly reduced the nocturnal surge of plasma melatonin and increased the levels of cortisol. The surge in plasma cortisol preceded the decrease in plasma melatonin concentration. These findings suggest a temporal relationship between plasma cortisol and melatonin responses to physical stress; the causal nature of this relationship remains to be elucidated.