We studied the combination of oleoyl-estrone with either dexfenfluramine, sibutramine or phentermine in overweight male rats treated for 10 days in order to determine whether they shared a mechanism of action. Oleoyl-estrone, dexfenfluramine and sibutramine decreased body weight and energy (essentially lipids); losses were higher when combined with oleoyl-estrone. Glycemia was maintained except under phentermine; oleoyl-estrone induced decreases in triacylglycerols, cholesterol, insulin and HOMA (homeostasis model assessment). Combination of oleoyl-estrone and sibutramine resulted in the loss of up to 29% body energy in 10 days. Energy expenditure was maintained. The effects of oleoyl-estrone and dexfenfluramine or sibutramine on appetite were substantially additive. All oleoyl-estrone-treated rats showed increased insulin sensitivity. In conclusion, combined treatment of overweight rats with oleoyl-estrone and sibutramine or dexfenfluramine results in a dramatic loss of weight and fat, whilst maintaining circulating energy homoeostasis.