Selective lactotrope dopamine D2 receptor disruption increases body weight and adipose accumulation

GUILLERMINA MARIA LUQUE,MARIA INÉS PEREZ- MILLÁN, ANA MARIA ORNSTEIN, CAROLINA CRISTINA AND DAMASIA BECÚ- VILLALOBOS.; MARIA INÉS PEREZ- MILLÁN; ANA MARIA ORNSTEIN; RUBINSTEIN, M.; BECÚ,-VILLALOBOS, D.

Dourado, SP

Congreso; First Brazilian International Symposium on Integrative; 2011

High prolactin (PRL) levels have been associated with increased food intake and body weight (BW), but in total dopamine receptor type 2 (D2R) knockout females (Drd2-/-), which have lifelong hyperpolactinemia, BW was decreased and food intake was minimally altered. Because these mice also have a decreased GH axis and non functional central D2Rs which might modify food intake, in collaboration with Dr. Rubinstein we generated transgenic mice with targeted deletion of the Drd2 gene in lactotropes (lacDrd2-/-) using Cre/LoxP technology. We found that BW was increased in lacDrd2-/- female mice compared to their Drd2flox/flox controls and to Drd2-/- mice. Daily food intake was also increased in lacDrd2-/- compared to Drd2flox/flox mice (3,47±0,10g compared to 3,02±0,17g), while no differences were found between Drd2-/- and wild-type (WT) paired female mice. LacDrd2-/- mice had similar body length than Drd2flox/flox mice, but higher visceral, gonadal and liver adipose accumulation (142%, 122% and 34% increase, respectively). Analysis of hypothalamic mRNA expression of genes associated to food intake showed that whereas hypothalamic precursor of orexin (Ppo) was decreased and Pomc increased in Drd2-/- mice compared to WT, in lacDrd2-/- no such differences were found. No differences in hypothalamic Npy mRNA expression were detected in any of the transgenic models. On the other hand, as described, Drd2-/- mice had decreased hypothalamic Ghrh mRNA, pituitary GH content, and serum IGF-I levels, while this axis was normal in lacDrd2-/- mice; and PRL levels were increased in both models. Our results show that in female mice total disruption of D2Rs produces two potentially anorexigenic events: a decrease in hypothalamic Ppo and an increase in Pomc levels. Very high PRL levels, which are orexigenic, probably counterbalance these effects, so that food intake is unaltered in this genotype. On the other hand, targeted deletion of pituitary D2R produces hyperprolactinemia but no changes in the expression of hypothalamic peptides related to food intake, and female mice present higher BW associated to increased fat mass and food intake. These results highlight the importance of functional central D2Rs in the orexigenic effect of high PRL levels.