Differential expression of dopamine D2 and D4 receptor and tyrosine hydroxylase mRNA in mice prone, or resistant, to chronic high-fat diet-induced obesity.

The present study examined brain dopamine D2 and D4 receptor and tyrosine hydroxylase (TH) mRNA expression in chronic high-fat diet-induced obese (cDIO) and obese-resistant (cDR) mice. Twenty-eight mice were fed a high-fat diet (HF: 40% of calories from fat) for 6 weeks and then classified as cDIO (n = 8) or cDR (n = 8) mice according to the highest and lowest body weight gainers, respectively. Seven mice were fed a low-fat diet (LF: 10% of calories from fat) and used as controls. After 20 weeks of feeding, visceral fat per gram of initial body weight was significantly higher in the cDIO group (ratio: 0.25, 0.09, and 0.04; P < 0.01 cDIO vs. cDR and LF, respectively). Using quantitative in situ hybridization techniques, the levels of D2 and D4 receptor and tyrosine hydroxylase (TH) mRNAs were measured in multiple brain sections. The cDIO mice had a significantly higher level of D2 receptor mRNA expression in the core of the nucleus accumbens (AcbC, +16%) and ventral parts of caudate putamen (CPu, 21% and 24%) compared to the cDR and LF mice. The levels of D2 receptor mRNA expression in the AcbC and ventromedial part of the CPu were positively related to the final body weight. This study is the first to systematically examine the D4 mRNA expression in the mouse brain using in situ hybridization method. D4 receptor mRNA expression in the ventromedial hypothalamic nucleus (VMH) and the ventral part of the lateral septal nucleus were also significantly higher in the cDIO mice compared to the cDR and LF mice (+31% and +60%; P < 0.05). TH mRNA expression was significantly higher in the ventral tegmental area (+17%, P </= 0.05) and locus caeruleus (+15%, P </= 0.05) of the cDIO mice compared to cDR mice. In conclusion, this study has demonstrated differentially regulated levels of D2 and D4 receptor and TH mRNA expression in specific brain regions of cDIO and cDR mice. It provides evidence that D4 receptors may play an important role influencing satiety via the mesohypothalamic pathway while the D2 receptor may regulate reward and motor centers via mesolimbic and nigrostriatal pathways. These findings contribute to the understanding of the role of these receptors in susceptibility, or resistance, to diet-induced obesity.