Dehydroepiandrosterone (DHEA) has been shown to alter hypothalamic monoamines and reduce energy intake (EI) in Zucker rats (ZRs). We hypothesized that a metabolite of DHEA, delta 4-Androstenedione (delta 4), may mediate these effects. Male lean and obese ZRs (LZR, OZR) were fed control chow (CC) for 7 days, during which basal EI was recorded, various concentrations of delta 4 for 7 days, during which 0.6 and 0.3% delta 4 reduced EI significantly, and CC for 7 days, which resulted in a return of EI to basal levels. After delta 4 administration, neurotransmitter contents of various hypothalamic areas were determined. Serotonin (5-HT) has been shown to be correlated with feeding inhibition, and we have shown DHEA to increase lateral hypothalamic 5-HT synthesis; however, after 1 day and 7 days of delta 4, the OZR exhibited an increased metabolism, not synthesis, of 5-HT in the lateral and paraventricular hypothalamus, respectively, delta 4 was compared to DHEA in a macronutrient self-selection study with female OZRs. One group was injected intraperitoneally (IP) with sesame oil (control), another with DHEA (100 mg/kg), and another with delta 4 (100 mg/kg). Previous studies have shown that DHEA decreases both EI and % calories from fat. In this study, delta 4 decreased % calories from fat, but did not decrease total EI. Contrary to DHEA's effect of reducing serum insulin through 28 days of treatment, delta 4 in chow reduced insulin only acutely (1 day). We conclude, based on these differences, that DHEA has unique effects not mediated by its metabolite, delta 4-Androstenedione.