Perinatal protein restriction reduces the inhibitory action of serotonin on food intake

Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5‐HT) in the brain. Inasmuch as 5‐HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5‐HT are altered by protein malnutrition. Pregnant Sprague‐Dawley rats were fed ad libitum either a control (20% protein) or a low‐protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of dl‐fenfluramine (dl‐FEN), an anorexic compound that blocks the reuptake of 5‐HT and stimulates its release. Male offspring born to protein‐restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. dl‐FEN dose‐dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of dl‐FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of dl‐FEN on c‐fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low‐protein‐fed rats. Further pharmacological analysis with selective 5‐HT1B and 5‐HT2C receptor agonist showed that the reduced anorexic effects of 5‐HT in malnourished animals were coupled to a desensitization of 5‐HT1B receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5‐HT on food intake.