Serotonin (5-HT) plays a regulatory role in coordinating the neural circuits regulating energy balance, with differences in both 5-HT availability at the synapse and the activity of 5-HT receptors mediating anorectic (via POMC/CART activation) and orexigenic (via NPY/AgRP activation) responses. In conditions of overweight and obesity the control of energy balance is clearly deregulated, and serotonergic modulation appears to make a significant contribution to weight gain. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) that increases 5-HT availability in the synaptic cleft may thus have potential effects on energy balance. Our aim was to use an overfeeding model to investigate the effects of chronic FLX treatment on energy balance-related parameters regulated by hypothalamic neuropeptides. Nursing male Wistar rats were assigned to normofed (9 pups/dam) or overfed (3 pups/dam) groups beginning at 3 days of age and continuing until 21 days of age, when commercial chow and water were made available ad libitum until experimental treatments were begun. From 39 through 59 days of age groups were divided according to pharmacological treatment: 1) NV group, normofed + vehicle solution (NaCl 0.9%, 10 ml/kg b.w.), 2) NF group, normofed + FLX (10 mg/kg b.w., in vehicle solution, 10 ml/kg b.w.) 3), OV, overfed + vehicle solution and 4) OF, overfed + FLX. At 60 days of age, body weight, white and brown adipose tissue content, and food intake were determined, and serum biochemical parameters and hypothalamic neuropeptide gene expression were measured. Results showed that FLX induced reductions in several murinometric indices, improvement of adipose profile, hypophagic behavior, reduction in serum parameters, and positive modulation of hypophagia-related genes. These data suggest that the beneficial effects of FLX-treatment on overfeeding-induced physical and behavioral effects in rats was due to hypothalamic alterations that led to improvement in energy balance in animals with a compromised metabolism.
