Corticotropin-releasing hormone (CRH) transgenic mice display hyperphagia with increased Agouti-related protein mRNA in the hypothalamic arcuate nucleus

Although glucocorticoid-induced hyperphagia is observed in the patients with glucocorticoid treatment or Cushing's syndrome, its molecular mechanism is not clear. We thus explored the expression of neuropeptide mRNAs in the hypothalamus related to appetite regulation in CRH over-expressing transgenic mice (CRH-Tg), a model of Cushing's syndrome. We measured food intake, body weight (including body fat weight) and plasma corticosterone levels in CRH-Tg and their wild-type littermates (WT) at 6 and 14 weeks old. We also examined neuropeptide Y (NPY), proopiomelanocortin (POMC) and Agouti-related protein (AgRP) mRNAs in the arcuate nucleus (ARC) using in situ hybridization. Circulating corticosterone levels in CRH-Tg were markedly elevated at both 6 and 14 weeks old. Body fat weight in CRH-Tg was significantly increased at 14 weeks old, which is considered as an effect of chronic glucocorticoid excess. At both 6 and 14 weeks old, CRH-Tg mice showed significant hyperphagia compared with WT (14w old: WT 3.9 +/- 0.1, CRH-Tg 5.1 +/- 0.7 g/day, p<0.05). Unexpectedly, NPY mRNA levels in CRH-Tg were significantly decreased at 14 weeks old (WT: 1571.5=111.2, CRH-Tg: 949.1 +/- 139.3 dpm/mg, p<0.05), and there were no differences in POMC mRNA levels between CRH-Tg and WT. On the other hand, AgRP mRNA levels in CRH-Tg were significantly increased compared with WT at both ages (14w old: WT 365.6 +/- 88.6, CRH-Tg 660.1 +/- 87.2 dpm/mg, p<0.05). These results suggest that glucocorticoid-induced hyperphagia is associated with increased hypothalamic AgRP. Our results also indicate that hypothalamic NPY does net have an essential role in the increased food intake during glucocorticoid excess.