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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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 1

ArcPomc–/– mice are obese and hyperphagic due to an impairment in hypothalamic Pomc expression.

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ArcPomc–/– mice are obese and hyperphagic due to an impairment in hypoth...
(A) ArcPomc– allele contains an insertion of a neomycin resistance cassette (neo), flanked by loxP sites, interrupting Pomc neuronal enhancer activity. Red oval, neuronal Pomc enhancer 1 (nPE1); asterisk, deletion of nPE2 (18); gray oval, Pomc promoter/pituitary enhancer; black rectangles, Pomc exons; arc and pit arrows, arcuate and pituitary Pomc transcription, respectively; X, inhibition of arcuate Pomc transcription. (B) Sections of arcPomc+/– and arcPomc–/– mice. Top two rows (POMC-EGFP): Mice transgenic for POMC-EGFP (19); upper panels show endogenous EGFP in POMC cells of coronal brain sections, and lower panels correspond to ACTH immunofluorescence (red, “POMC”) of the same slices. Arc, arcuate neurons. Third row (Pit): Pituitaries with ACTH immunofluorescent corticotrophs of the anterior lobe (AL) and melanotrophs of the intermediate lobe (IL). Fourth row (E14): Sagittal sections of E14 mice showing ACTH immunostaining. Pit, pituitary; 3v, third ventricle. Scale bars: 200 μm for lower- and 50 μm for higher-magnification photomicrographs. (C) Body weight curves of Pomc+/+, arcPomc+/–, and arcPomc–/– mice. ArcPomc–/– mice are obese (RMA, genotype × time effect: P < 0.001 for arcPomc–/– vs. Pomc+/+ and vs. arcPomc+/– for both sexes). (D) Average daily food intake measured during 3 consecutive weeks at 5–6 months of age. (E) Hypothalamic Pomc mRNA expression normalized to 18S rRNA, relative to Pomc+/+, in arbitrary units (AU). (D and E) n = 4–6 for each group. Error bars correspond to SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (OWA).