Decreased ventromedial hypothalamic (VMH) serotonergic activity occurs in genetic and diet-induced animal models of obesity. We previously found that this activity was lower in adult and in 12-day-old Zucker fa/ favs. Fa/ Fapups, the fa/ faanimals being identified by their greater adiposity. In the present study, we evaluated fa/ farats (Brown Norway-Zucker hybrids) at ages 2, 4, 7, and 12 days to test the hypothesis that lower VMH serotonergic activity occurs before increased adiposity and/or attenuated energy expenditure. Our results negate this hypothesis. VMH serotonergic activity showed no consistent genotype differences even at 12 days of age. In contrast, by day 7, fa/ favs. Fa/ Fapups had higher serum leptin concentrations, greater percent body fat, lower resting and cold-induced energy expenditure, and lower activity of brown fat thyroxine 5′-deiodinase, an enzyme that converts thyroxine to triiodothyronine. We conclude that the onset of increased adiposity induced by the fa gene does not require decreased VMH serotonergic activity and that the lower serotonergic activity seen in older fa/ fapups may be secondary to metabolic consequences of the disruption of the leptin regulatory pathway.