Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, a key neurotransmitter in the regulation of food intake. This study examined tyrosine hydroxylase mRNA expression in obese mice fed a high-fat diet. After 8 week feeding of high-fat diet mice were classified as diet-induced obese and obese-resistant according to body weight gain. They were then placed on different dietary interventions including a high-fat diet, a low-fat diet and an energy-restricted high-fat diet for six weeks. The control group was fed a low-fat diet. The results revealed that tyrosine hydroxylase mRNA expression was significantly decreased in the ventral tegmental area (VTA), ventromedial hypothalamic nucleus (VMH), and substantia nigra (SN) of the high-fat diet-induced obese (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 29%, ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 26% and ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 26%) and obese-resistant mice (ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 21%, ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 24% and ÃÂÃÂÃÂÃÂÃÂÃÂÃÂÃÂ¿ 18%) compared to controls. After switching the diet from high to low-fat diet tyrosine hydroxylase mRNA was increased in the VTA, VMH, and SN of the diet-induced obese mice and in the VMH, and SN of the obese-resistant mice. Energy restriction, even with high-fat feeding, reduced tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN compared to controls. In addition, tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN showed a significant negative correlation with plasma leptin levels. This study suggests that the up- or down-regulation of tyrosine hydroxylase mRNA expression in the VTA, VMH, and SN is mainly due to the intake of macronutrient type rather than body weight.