Early genetic rescue of extremely obese mice restores normal feeding behavior and body weight

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 billion people over the world and is increasing in children and adolescents. Chronic overweight not only decreases life quality but also life expectancy since it predisposes to type-2 diabetes, hypertension, heart disease and cancer. A major difficulty of obesity treatments is that patients stop losing weight after a period of responsiveness and often experience a rebound. Although the generalized failure of obesity treatments cannot be readily explained, it is conceivable that after extreme and prolonged deviations from normal body weight the central energy balance homeostat exceeds its elastic limit. To test this hypothesis, we generated a reversible knockout mouse model of early onset obesity. These mice are unable to express the proopiomelanocortin gene (Pomc) in hypothalamic neurons (arcPomcKO) but maintain normal pituitary Pomc expression. ArcPomcKO mice are hyperphagic and extremely obese due to central anorexigenic melanocortin deficiency. To study the age of treatment as a determinant of healing success, arcPomcKO mice were crossed with transgenic mice expressing a tamoxifen-inducible Cre recombinase. Compound arcPomcKO:Cre-ERT mice recovered central melanocortins upon tamoxifen treatment. We injected tamoxifen to three groups of arcPomcKO:Cre-ERT mice, starting at 25, 60 and 180 days-old, respectively. Pomc rescued at P25 completely prevented obesity development, indicating that early recovery of central Pomc reestablishes normal homeostasis of energy balance. Although obese mice receiving tamoxifen at P60 or P180 became almost normophagic and lost considerable weight, they remained heavier than age-matched control animals. Female mice rescued at P60 reduced their overweight from 61% to 17% whereas males overweight dropped from 54 % to 24 %. P180 rescued mice showed an even greater weight loss but remained heavier than P60 rescued mice. Oxygen consumption corrected by lean mass (VO2, ml/kg/hr) showed no difference between arc-PomcKO:Cre-ERT and WT male mice. In obese arc-PomcKO:Cre- ERT females, however, there was a significant 10% reduction of VO2 compared to WT mice before treatment and this difference remained after treatment. Peripheral parameters related to obesity co-morbidities such as fat stores, leptinemia, insulinemia and glycemia were also highly improved after Pomc rescue. Altogether, ourstudy shows that restoration of Pomc expression reestablishes satiety control and energy balance and highlights the importance of early genetic rescue to obtain complete restoration of body weight homeostasis.