Inhibitory effects of anti-VEGF strategies in experimental dopamine resistant prolactinomas

GUILLERMINA LUQUE; MARÍA INÉS PÉREZ MILLÁN; ANA ORNSTEIN; CAROLINA CRISTINA; DAMASIA BECU VILLALOBOS

Boston, MA

Congreso; The Endocrine Society´s Annual Meeting; 2011

High prolactin levels have been associated with increased food intake and body weight, but in total dopamine receptor type 2 (D2R) knockout females (Drd2-/-), which have lifelong hyperpolactinemia, body weight was decreased and food intake was minimally altered. Because these mice have also a decreased GH axis and non functional central D2Rs which might modify food intake, we generated transgenic mice using Cre-LoxP technology in which the Drd2 gene was specifically deleted in lactotrope cells (lacDrd2-/-). We then compared body weight and nose-anus length, visceral, gonadal and liver adipose fat, food intake, prolactin and GH levels, and hypothalamic Pomc, orexin precursor (Ppo) and Npy expression in female Drd2-/- and lacDrd2-/- mice compared to the appropriate controls. Body weight and daily food intake in lacDrd2-/- were higher than in Drd2flox/flox mice, while body weight and daily food intake was similar in Drd2-/- compared to wild-type 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 Ppo was decreased and Pomc increased in Drd2-/- mice, indicating two anorexigenic events, in lacDrd2-/- no such differences were found. No differences in hypothalamic Npy mRNA expression were detected in either transgenic model. On the other hand, as described, Drd2-/- mice had decreased hypothalamic Ghrh mRNA, pituitary GH content, and serum IGF-I levels, while the GHRH-GH-IGF-I axis was normal in lacDrd2-/- mice. Our results show that in female mice total disruption of D2Rs produces two potentially anorexigenic events: a decrease in hypothalamic orexin expression and increased Pomc levels. Very high prolactin 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 body weight associated to increased fat mass and food intake. These results highlight the importance of central D2Rs in the orexigenic and adipogenic effects of high prolactin levels.