Early genetic rescue of extremely obese POMC-deficient mice is critical for successful recovery of normal feeding behavior and body weight
Viviana Bumaschny1,2, Flavio de Souza1, Vanina Rodríguez1, Malcolm Low3 & Marcelo Rubinstein1,2
A major difficulty of obesity treatments is that patients stop losing weight after a period of responsiveness and often experience a rebound. This could be caused by an impairment in energy balance circuits that becomes irreversible as obesity progresses. 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 (CNS-Pomc−/−) but maintain normal pituitary Pomc expression. They are hyperphagic and extremely obese due to central anorexigenic melanocortin deficiency. To restore central Pomc expression, CNS-Pomc−/− mice were crossed with transgenic mice expressing a tamoxifen-inducible Cre recombinase. Compound CNS-Pomc−/−: Cre-ERT mice recover the production of central melanocortins upon tamoxifen treatment. To test Pomc restoration at different ages, we injected tamoxifen to CNS-Pomc−/−: Cre-ERT at postnatal days 25 or 60 (P25 or P60). No CNS-Pomc−/−: Cre-ERT mice of either sex treated with tamoxifen at P25 developed obesity, indicating that early recovery of central Pomc completely prevents energy homeostasis imbalance. In contrast, despite losing some weight, obese mice treated at P60 remained heavier than control animals. At the beginning of treatment (P60), CNS-Pomc−/−: Cre-ERT female and male mice were 67% and 66% heavier than their WT littermates, whereas four months later this difference dropped to 10% and 41%, respectively. Although CNS-Pomc−/−: Cre-ERT mice treated at P60 dramatically reduced their food intake, they remained hyperphagic. In females, tamoxifen treatment reduced food intake from 5.1±0.28 g/day to 3.7±0.28, somewhat more than WT females that ate 3.2±0.28 g/day (P<0.0001). Males reduced their food intake from 5.4±0.34 to 4.1±0.29 g/day but did not reach normal WT male values of 3.1±0.18 g/day (P<0.0001). The differences between sexes and treatment ages were observed despite similar recovery in the number of neurons that express PomcP25 treated males, 69%; P25 treated females, 63%; P60 treated males, 73%; and P60 treated females, 77%. Our results indicate that the plasticity of satiety circuits necessary to restore normal homeostatic values is progressively lost between weaning and adulthood in mice with monogenic obesity.