Bumaschny and colleagues found that restoration of neuronal Pomc expression in lean juvenile mice completely prevented the subsequent development of obesity. However, the ability of hypothalamic Pomc reexpression to normalize body weight was progressively attenuated as the age of Pomc rescue was delayed and the obesity was allowed to continue. Given that the degree of Pomc restoration remained constant among all age groups, Bumaschny and colleagues suspected that the increased adiposity and the metabolic changes associated with obesity played a major role in the blunted phenotypic responses to Pomc rescue. In an innovative approach, the authors tested this hypothesis using a caloric restriction regimen to delay the onset of obesity in older Pomc-deficient mice. At P60, when obesity is evident in Pomc-deficient mice fed ad libitum and Pomc reexpression can only partially alleviate the development of obesity, the calorie-restricted Pomc-deficient mice had body weight comparable to that of wild-type controls. Furthermore, Pomc restoration in calorie-restricted mice successfully prevented the subsequent development of obesity. These results therefore indicate that the preceding development of obesity and its cumulative effects, but not age, are responsible for the attenuated phenotypic responses to Pomc rescue in older Pomc-deficient mice (Figure ).
Pomc deletion in the hypothalamus leads to obesity in ad libitum fed mice.
A key point of the work of Bumaschny et al. is the potential importance of early intervention for the effective treatment of obesity and its associated comorbid conditions. This is particularly relevant in our society today. For example, more than one-third of children and adolescents are overweight or obese in the United States (9
), and the rates are increasing. If left unmanaged, obesity in childhood is likely to persist into adulthood (10
), and, as indicated by Bumaschny et al., these individuals may become resistant to later medical interventions. Indeed, the authors’ finding that, despite the significant normalization of hyperphagia, the improvement in body weight progressively waned as the restoration of Pomc
expression was delayed supports the notion that obesity is a self-perpetuating condition that needs early management and intervention. Finally, it has become increasingly clear that alterations in the metabolic state of mothers during critical periods of fetal development, both in utero and in the early postnatal period, can have long-lasting effects in the offspring (11
). Thus, early intervention to combat obesity may become even more of an issue as more and more children are born in the context of maternal obesity and diabetes.