Deletion of dopamine D2 receptors in pituitary lactotropes increases food intake, body weight and adiposity

LUQUE GM; PEREZ-MILLAN MI; RUBINSTEIN M; BECU-VILLALOBOS D

Houston

Congreso; The Endocrine Society s 94rd Annual Meeting; 2012

Prolactin secretion is tonically inhibited by dopamine acting on lactotrope dopamine D2 receptors (D2Rs). Consequently, female mice lacking D2Rs (Drd2-/-) exhibit chronic hyperprolactinemia and pituitary lactotrope hyperplasia. Although hyperprolactinemia has been associated with increased food intake and body weight, Drd2-/- female mice display normal body weight probably because of multiple overlapping phenotypes derived from the absence of D2Rs from all brain areas and peripheral tissues. To dissect the importance of lactotrope D2Rs in food intake and body weight regulation we generated mutant mice carrying targeted Drd2 deletions specifically in lactotropes (lacDrd2-/-) using Cre/LoxP technology. As expected, lacDrd2-/- females are hyperprolactinemic whereas neuronal and peripheral D2Rs appear to function normally as determined by haloperidol-induced catalepsia and insulin serum levels. In addition,  lacDrd2-/- females showed increased body weight gain and adiposity in comparison with age-matched Drd2loxP/loxP and Drd2-/- female mice. LacDrd2-/- mice had similar body length than Drd2loxP/loxP mice, but increased gonadal and retroperitoneal fat pads, as well as heavier livers (142%, 122% and 34% increase, respectively). Daily food intake was also increased in lacDrd2-/- compared to Drd2loxP/loxP mice (3.47±0.10 g vs. 3.02±0.17 g). Hypothalamic expression of genes associated to food intake showed that precursor of orexin (Ppo) mRNA decreased in Drd2-/- mice but not in lacDrd2-/-. In contrast, hypothalamic Npy mRNA was increased only in lacDrd2-/- female mice. Thus, the increase in food intake, body weight and adiposity observed in lacDrd2-/- females in comparison to Drd2-/- mice highlights the importance of functional central D2Rs in the orexigenic effect promoted by high prolactin levels and suggest that the increased levels of Npy mRNA found in lacDrd2-/- female mice are probably involved in these phenotypes.