Pomc to the Rescue

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Science Translational Medicine  07 Nov 2012:
Vol. 4, Issue 159, pp. 159ec203
DOI: 10.1126/scitranslmed.3005251

Obesity has reached epidemic proportions, affecting the health of more than one-third of U.S. adults and 17% of children and adolescents. Prior studies suggest that chronic obesity may trigger compensatory physiological responses that promote the state of constant positive energy balance. Although these observations may explain why sustained weight management is a challenge for so many obese patients, the precise mechanisms that underlie recidivism after dieting and obesity treatment remain unknown.

Now, Bumaschny et al. generate a new reversible genetic mouse model of early-onset severe obesity by selectively blocking the expression of a single gene, proopiomelanocortin (Pomc) in hypothalamic neurons. Pomc is highly expressed in the pituitary gland and hypothalamus of all vertebrates. In both humans and rodents, mutations in the Pomc gene lead to severe hyperphagia (increased appetite), early-onset obesity, and adrenal insufficiency—a shortage of hormones that regulate adrenal function, which results from a deficiency in another Pomc product, adrenocorticotropic hormone. The authors found that restoring neuronal Pomc expression in young mice normalized food intake and body weight, thus preventing the development of obesity. Hypothalamic Pomc rescue also reduced comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis (fatty liver disease) and normalized locomotor activity. However, the improvement in body weight was progressively attenuated as the age of Pomc rescue was delayed and obesity was allowed to continue.

These results suggest the importance of early intervention and weight management in children to prevent obesity and its associated comorbid conditions. Although Pomc restoration normalized food intake, effectiveness of Pomc rescue to normalize body weight and adiposity declined once obesity was established. This study provides new insights into the mechanisms underlying obesity-treatment refractoriness and begins to shed some light on why it can be increasingly difficult to lose weight over time.

V. F. Bumaschny et al., Obesity-programmed mice are rescued by early genetic intervention. J. Clin. Invest. 122, 4203–4212 (2012). [PubMed]

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