Genetically Mediated Reversal of Obesity by Eutopic Proopiomelanocortin Expression is Associated with Normalization of Food Intake and Locomotor Activity but not Oxygen Consumption

MIHO YAMASHITA; VERONICA OTERO-CORCHON; VIVIANA F. BUMASCHNY; MARCELO RUBINSTEIN; MALCOLM LOW

Boston

Congreso; The Endocrine Society's 93rd Annual Meeting (ENDO 2011); 2011

The Endocrine Society

Body: Body weight is remarkably stable under normal physiological conditions, suggesting the existence of an intrinsic set-point. We generated a reversible genetic mouse model of early onset obesity to examine the role of brain proopiomelanocortin (POMC) peptides in the set-point mechanism. Mice selectively lacking Pomc expression in hypothalamic arcuate (ARC) neurons (ARC-PomcKO) were crossed with transgenic mice expressing a tamoxifeninducible Cre recombinase. Compound ARC-PomcKO:Cre-ERT mice are hyperphagic and obese due to central melanocortin deficiency. The mice recover expression of ARC Pomc after tamoxifen (50 mg/kg i.p. x 5 daily doses) to similar levels regardless of their age at treatment, however the improvement in body weight is progressively attenuated as treatment age is delayed from weaning to adulthood. In this study, we evaluated the energy balance of ARC-PomcKO:Cre-ERT mice before (age 7 wk) and after (age 12 wk) tamoxifen treatment at age 8 wk to determine the basis for incomplete restoration of normal body weight. Body composition, food intake, locomotor activity and metabolic rate were evaluated serially. BW of ARC-PomcKO:Cre-ERT male and female mice were 57% and 81% greater, respectively, than WT:Cre-ERT controls. These differences dropped to 12% and 21%, respectively, after tamoxifen treatment mainly due to the loss of fat. Male mice reduced their food intake from 5.7 0.3 to 4.5 0.3 g/day (P<0.01), which was equivalent to WT (4.8 0.4 g/day). Female mice reduced their food intake from 5.7 0.3 to 3.7 0.3 g/day (P<0.01), which was also equivalent to WT (4.1 0.1 g/day). ARCPomcKO: Cre-ERT mice of both sexes showed significant increases following treatment in their originally low locomotor activity to levels that were not different from WT mice. In males, there was no difference between ARC-PomcKO:Cre-ERT and WT mice in oxygen consumption corrected by lean mass (VO2, ml/kg/hr) either before or after treatment. However, there was a significant 10% reduction of VO2 in obese female ARC-PomcKO:Cre- ERT compared to WT mice before treatment (P<0.01) and this difference remained after treatment. These data suggest that an impairment of metabolic rate persists despite the normalization of food intake and locomotor activity following genetic rescue of ARC Pomc expression. Future studies are needed to explain the disassociation between these variables for their normalization once an obesity state has been established.