The present study examined the levels of 5-HT(2A) and 5-HT(2C) (2A and 2C receptors of 5-hydroxytryptamine; serotonin) receptor messenger RNA (mRNA) expressions in the brain of chronic high-fat diet-induced obese (DIO) and obese-resistant (DR) mice. Thirty-one mice were used in this study. Twenty-four mice were fed with a high-fat diet (HF: 40% of calories from fat) for 4 weeks and then classified as the DIO (n = 8) or DR (n = 8) mice according to the highest and lowest body weight (BW) gainers. Seven mice were placed on a low-fat diet (LF: 10% of calories from fat) and were used as controls. After 20 weeks of feeding, the visceral fat accumulation was 620 +/- 42 mg in the DIO group versus 198 +/- 89 mg in the DR and 84 +/- 18 mg in the LF groups. Using quantitative in situ hybridization techniques, levels of 2A and 2C serotonin (5-HT) receptor mRNAs were measured in multiple brain sections of mice from the three groups. Most regions did not differ between groups but, importantly, the DIO mice had a significantly higher level of 5-HT(2A) receptor mRNA expression in the olfactory nucleus (Olf) compared to the DR and LF mice (+30% and +37%, respectively). The levels of Olf 5-HT(2A) receptor mRNA expression were related to body fat mass. The level of 5-HT(2C) mRNA receptor expression in the ventromedial hypothalamic (VMH) nucleus was 40% higher in the DIO mice than in the LF mice. Furthermore, the 5-HT(2C) receptor mRNA expression in the posterodorsal part of the medial amygdaloid (MePD) nucleus was 25% higher in the DIO mice than in the DR mice. The level of VMH 5-HT(2C) receptor mRNA expression was correlated with body fat mass. In conclusion, this study has demonstrated differentially regulated levels of the 5-HT(2A) and 5-HT(2C) receptor mRNA expressions in the specific brain regions of the DIO and DR mice. It provides neural anatomical bases that the 5-HT(2C) receptors positively influence satiety center (VMH) while the 5-HT(2A) receptor regulates olfactory sensory effects. The findings also assist us to understand the role of these receptors in mice susceptible or resistant to diet-induced obesity.