Elevated glucocorticoid production and reduced hypothalamic POMC mRNA can cause obese phenotypes. Conversely, adrenalectomy can reverse obese phenotypes caused by the absence of leptin, a model in which glucocorticoid production is elevated. Adrenalectomy also increases hypothalamic POMC mRNA in leptin-deficient mice. However most forms of human obesity do not appear to entail elevated plasma glucocorticoids. It is therefore not clear if reducing glucocorticoid production would be useful to treat these forms of obesity. We hypothesized that adrenalectomy would increase hypothalamic POMC mRNA and reverse obese phenotypes in obesity due to a high-fat diet as it does in obesity due to leptin deficiency.

Retired breeder male mice were placed on a high-fat diet or a low-fat diet for two weeks, then adrenalectomized or sham-adrenalectomized. The high-fat diet increased body weight, adiposity, and plasma leptin, led to impaired glucose tolerance, and slightly stimulated hypothalamic proopiomelanocortin (POMC) expression. Adrenalectomy of mice on the high-fat diet significantly reduced plasma corticosterone and strikingly increased both pituitary and hypothalamic POMC mRNA, but failed to reduce body weight, adiposity or leptin, although slight improvements in glucose tolerance and metabolic rate were observed.

These data suggest that neither reduction of plasma glucocorticoid levels nor elevation of hypothalamic POMC expression is effective to significantly reverse diet-induced obesity.