Early genetic rescue of extremely obese mice restores normal feeding

RUBINSTEIN M; CASAS-CORDERO R; YAMASHITA M; DE SOUZA FS; OTERO-CORCHON V; LOW MJ; BUMASCHNY VF

Washington, DC

Congreso; Neuroscience 2011; 2011

Society For Neuroscience

Obesity is a chronic metabolic disorder that affects almost half a billionpeople over the world and is increasing in children and adolescents.Chronic overweight not only decreases life quality but also life expectancysince it predisposes to type-2 diabetes, hypertension, heart disease andcancer. A major difficulty of obesity treatments is that patients stop losingweight after a period of responsiveness and often experience a rebound.Although the generalized failure of obesity treatments cannot be readilyexplained, it is conceivable that after extreme and prolonged deviationsfrom normal body weight the central energy balance homeostat exceeds itselastic limit. To test this hypothesis, we generated a reversible knockoutmousemodel of early onset obesity. These mice are unable to express theproopiomelanocortin gene (Pomc) in hypothalamic neurons (arcPomcKO)but maintain normal pituitary Pomc expression. ArcPomcKO mice arehyperphagic and extremely obese due to central anorexigenic melanocortindeficiency. To study the age of treatment as a determinant of healingsuccess, arcPomcKO mice were crossed with transgenic mice expressing atamoxifen-inducible Cre recombinase. Compound arcPomcKO:Cre-ERTmice recovered central melanocortins upon tamoxifen treatment. Weinjected tamoxifen to three groups of arcPomcKO:Cre-ERT mice, startingat 25, 60 and 180 days-old, respectively. Pomc rescued at P25 completelyprevented obesity development, indicating that early recovery of centralPomc reestablishes normal homeostasis of energy balance. Although obesemice receiving tamoxifen at P60 or P180 became almost normophagic andlost considerable weight, they remained heavier than age-matched controlanimals. Female mice rescued at P60 reduced their overweight from 61 %to 17 % whereas males overweight dropped from 54 % to 24 %. P180rescued mice showed an even greater weight loss but remained heavierthan P60 rescued mice. Oxygen consumption corrected by lean mass (VO2,ml/kg/hr) showed no difference between arc-PomcKO:Cre-ERT and WTmale mice. In obese arc-PomcKO:Cre- ERT females, however, there was asignificant 10% reduction of VO2 compared to WT mice before treatmentand this difference remained after treatment. Peripheral parameters relatedto obesity co-morbidities such as fat stores, leptinemia, insulinemia andglycemia were also highly improved after Pomc rescue. Altogether, ourstudy shows that restoration of Pomc expression reestablishes satietycontrol and energy balance and highlights the importance of early geneticrescue to obtain complete restoration of body weight homeostasis.