Reversal of physiological deficits caused by diminished levels of peptidylglycine α-amidating monooxygenase by dietary copper

Amidated peptides are critically involved in many physiological functions. Genetic deletion of peptidylglycine α-amidating monooxygenase (PAM), the only enzyme that can synthesize these peptides, is embryonically lethal. The goal of the present study was the identification of physiological functions impaired by haploinsufficiency of PAM. Regulation of the hypothalamic-pitu- itary-thyroid axis and body temperature, functions requiring contributions from multiple ami-dated peptides, were selected for evaluation. Based on serum T ₄ and pituitary TSH-β mRNA levels, mice heterozygous for PAM (PAM ^+/-) were euthyroid at baseline. Feedback within the hypotha-lamic-pituitary-thyroid axis was impaired in PAM ^+/- mice made hypothyroid using a low iodine/propylthiouracil diet. Despite their normal endocrine response to cold, PAM ^+/- mice were unable to maintain body temperature as well as wild-type littermates when kept in a 4 C environment. When provided with additional dietary copper, PAM ^+/- mice maintained body temperature as well as wild-type mice. Pharmacological activation of vasoconstriction or shivering also allowed PAM ^+/- mice to maintain body temperature. Cold-induced vasoconstriction was deficient in PAM ^+/- mice. This deficit was eliminated in PAM ^+/- mice receiving a diet with supplemental copper. These results suggest that dietary deficiency of copper, coupled with genetic deficits in PAM, could result in physiological deficits in humans.