Obesity-programmed mice are rescued by early genetic intervention
Viviana F. Bumaschny, … , Marcelo Rubinstein, Malcolm J. Low
Viviana F. Bumaschny, … , Marcelo Rubinstein, Malcolm J. Low
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4203-4212. https://doi.org/10.1172/JCI62543.
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Research Article

Obesity-programmed mice are rescued by early genetic intervention

Abstract

Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity.

Authors

Viviana F. Bumaschny, Miho Yamashita, Rodrigo Casas-Cordero, Verónica Otero-Corchón, Flávio S.J. de Souza, Marcelo Rubinstein, Malcolm J. Low

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Figure 5

Serial measurements of metabolic parameters before and 4 weeks after TAM treatment in a cohort of female P60 mice.

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Serial measurements of metabolic parameters before and 4 weeks after TAM...
(A) Body composition measured by NMR. ***P < 0.001, pairwise comparison of body fat by Bonferroni’s post hoc test. (B) Total locomotor activity in the horizontal plane measured by infrared beam breaks in the CLAMS chambers. The line graphs show average hourly activity counts over the final 24-hour period of a 72-hour continuous measurement. The dark period between 6 p.m. and 6 a.m. is indicated by the black bar below the x axis. The bar graph on the right shows the average hourly activity over the entire 12-hour dark period. ***P < 0.001, effect of TAM treatment in arcPomc–/–:Cre-ERT mice. (C) VO2 corrected to lean body mass (LBM) determined by indirect calorimetry in the CLAMS chambers. The line graphs show average hourly VO2 over the final 24-hour period of a 72-hour continuous measurement. The dark period between 6 p.m. and 6 a.m. is indicated by the black bar under the x axis. The bar graph on the right shows the average hourly VO2 over the entire 12-hour dark period. **P < 0.01, pairwise comparison by Bonferroni’s post hoc test. None of the 3 genotypes of mice showed a significant change in VO2 after TAM treatment. All data shown are the mean ± SEM; n = 6–8 per genotype.