Bousquet-Moore D, Ma X M, Nillni E A, Czyzyk T A, Pintar J E, Eipper B A, Mains R E
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030-3401, USA.
Endocrinology. 2009 Apr;150(4):1739-47. doi: 10.1210/en.2008-1202. Epub 2008 Nov 20.
Amidated peptides are critically involved in many physiological functions. Genetic deletion of peptidylglycine alpha-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-pituitary-thyroid axis and body temperature, functions requiring contributions from multiple amidated peptides, were selected for evaluation. Based on serum T(4) and pituitary TSH-beta mRNA levels, mice heterozygous for PAM (PAM(+/-)) were euthyroid at baseline. Feedback within the hypothalamic-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.
酰胺化肽在许多生理功能中起着关键作用。肽基甘氨酸α-酰胺化单加氧酶（PAM）是唯一能合成这些肽的酶，其基因缺失在胚胎期是致死的。本研究的目的是确定PAM单倍剂量不足所损害的生理功能。选择评估下丘脑-垂体-甲状腺轴的调节和体温调节，这些功能需要多种酰胺化肽的参与。根据血清T4和垂体TSH-β mRNA水平，PAM杂合子小鼠（PAM(+/-)）在基线时甲状腺功能正常。使用低碘/丙硫氧嘧啶饮食使PAM(+/-)小鼠甲状腺功能减退后，下丘脑-垂体-甲状腺轴的反馈受损。尽管PAM(+/-)小鼠对寒冷有正常的内分泌反应，但当置于4℃环境中时，它们无法像野生型同窝小鼠那样维持体温。当给予额外的膳食铜时，PAM(+/-)小鼠能够像野生型小鼠一样维持体温。血管收缩或颤抖的药理激活也能使PAM(+/-)小鼠维持体温。PAM(+/-)小鼠的冷诱导血管收缩不足。在接受补充铜饮食的PAM(+/-)小鼠中，这种缺陷被消除。这些结果表明，膳食铜缺乏与PAM的基因缺陷相结合，可能导致人类生理缺陷。
