The melanocortin system is an important regulator of body weight and the hypothalamo-pituitary-thyroid (HPT) axis. The pro-opiomelanocortin (POMC)-null mouse, deficient in all POMC-derived peptides, including alpha-melanocyte stimulating hormone (alpha-MSH), has an obese phenotype. We studied the HPT axis of POMC-null mice, which has not been previously investigated. Because alpha-MSH has a stimulatory effect on the HPT axis, we hypothesised that these mice would have a down-regulated thyroid axis, consistent with a recent study of POMC-null humans. The activity of the HPT axis was studied by collecting blood, pituitaries and hypothalami from ad libitum fed, adult POMC-null, heterozygous and wild-type mice. POMC-null mice had significantly elevated plasma total T(4) (TT(4)) and free T(3) (fT(3)) with reduced plasma thyroid stimulating hormone (TSH), pituitary TSH content and hypothalamic thyrotrophin stimulating hormone (TRH) content compared to wild-type mice. No significant differences between heterozygous and wild-type mice were observed. POMC-null mice have an abnormal HPT axis, which may contribute to their hyperphagia and obesity. These abnormalities are in contrast to those observed in POMC-null humans. These findings support a role for the melanocortin system in the regulation of the HPT axis.