Background:Uncoupling protein-1 (UCP-1) is the index protein of the brown adipose tissue (BAT), used in the obesity studies. We evaluated the effects of thymoquinone (TQ), hydroalcoholic, and hexane extracts of Nigella sativa, on the UCP-1 gene expression in BAT, and also on the recovery from oxidative stress, due to a high-fat diet.Materials and Methods:Fifty mice were divided into five groups: the first group was fed with a usual diet and the second, third, fourth, and fifth groups with a high-fat diet, hydroalcoholic extract, hexane extract, and TQ, respectively. After completing the course, the lipid profile, paraoxonase 1 (PON1), serum total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. UCP-1 expression in BAT was evaluated at the gene and protein level.Results:The weight of mice, receiving TQ, hydroalcoholic, and hexane extracts, was decreased (P < 0.05), compared to the second group (P < 0.05). MDA was increased in the second group, compared to the first group (P < 0.05); however, TAC, liver catalase enzyme, and PON1 were decreased (P < 0.05). Furthermore, MDA of the third, fourth, and fifth groups had decreased, and the activity of PON1, liver catalase enzyme, and the amount of TAC was increased (P < 0.05). UCP-1 expression of the third and fourth groups was increased, compared to the second group (P < 0.05).Conclusion:The results suggest that TQ, hydroalcoholic, and hexane extracts of N. sativa have a protective and therapeutic role in the oxidative stress, caused by high-fat diets. The hydroalcoholic and hexane extracts can induce weight loss, by positively affecting UCP-1, at the gene and protein level.