Deletion of dopamine D2 receptors in pituitary lactotropes alters glucose homeostasis and increases adipose tissue accretion.

GUILLERMINA LUQUE; MARÍA INÉS PÉREZ MILLÁN; ANA ORNSTEIN; MARCELO RUBINSTEIN; DAMASIA BECU VILLALOBOS

San Francisco, CA

Congreso; The Endocrine Society´s Annual Meeting; 2013

Prolactin secretion is tonically inhibited by dopamine acting on lactotrope dopamine D2 receptors (D2Rs). High prolactin levels have been associated with increased food intake and body weight, but total D2R knockout female mice (Drd2-/-), which have lifelong hyperprolactinemia, display normal body weight probably because of compensating mechanisms related to the absence of D2Rs in brain areas and peripheral tissues. To test the importance of lactotrope D2Rs and prolactin in glucose metabolism and adipose tissue accretion we used mutant mice with targeted deletion of the Drd2 gene in lactotropes (lacDrd2-/-) generated by Cre/LoxP technology. Hyperprolactinemic lacDrd2-/- female mice showed increased body weight gain, food intake and adiposity in comparison with age-matched Drd2loxP/loxP and Drd2-/- female mice. Glucose homeostasis studies revealed that fasting and non-fasting glucose levels were normal in lacDrd2-/- female mice, but glucose intolerance after an ip load of 2g/kg was evidenced in lacDrd2-/- mice: blood glucose levels were significantly higher than those observed in Drd2loxP/loxP littermates at 30 and 60 min (p interaction [genotype x time]=0.000013). On the other hand, lactotrope knockout mice exhibited a conserved insulin tolerance test in vivo while pancreatic insulin content was significantly higher (p=0.0018) in comparison with Drd2loxP/loxP mice. In relation with the increased fat mass observed, we found that cholesterol levels were normal, but there was a significant increase in serum triglycerides (p=0.045) in lacDrd2-/- females compared with their controls.In addition, morphometry of adipose tissue showed that lacDrd2-/- female mice had a larger fat cells observed by comparing medians (2503 µm2 vs 1363 µm2, p