Degradation Paradigm of the Gut Hormone, Pancreatic Polypeptide, by Hepatic and Renal Peptidases.
Degradation Paradigm of the Gut Hormone, Pancreatic Polypeptide, by Hepatic and Renal Peptidases.
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DOI：
10.1210/en.2016-1827
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发表时间：
2017-06-01
期刊：
影响因子：
4.8
通讯作者：
Bloom S
中科院分区：
文献类型：
--
作者：
Cuenco J;Minnion J;Tan T;Scott R;Germain N;Ling Y;Chen R;Ghatei M;Bloom S
胰多肽（PP）是一种肠道激素，作用于Y 4受体以降低食欲。肥胖人群餐后PP增加减少，对外源性PP的厌食作用保持完全敏感。PP作为抗肥胖治疗的效用受到其短循环半衰期的限制。深入了解PP降解的机制有助于设计长效PP类似物。我们研究了肽酶在PP降解中的作用，以确定这些酶的抑制是否能增强PP的血浆水平和体内生物活性。二肽基肽酶IV（DPPIV）和脑啡肽酶（NEP）是两种能裂解PP的肽酶。限制两种肽酶的作用改善了PP和基于PP的类似物的体内厌食作用。这些发现表明，使用特异性抑制剂和/或设计抗DPPIV和NEP裂解的类似物来抑制PP的降解可能有助于开发PP作为抗肥胖药物疗法。研究了胰多肽（PP）在肾脏和肝脏组织制剂中的降解位点，并用于产生更持久的PP厌食类似物。
Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial increase in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an anti-obesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded could aid in the design of long-acting PP analogs. We investigated the role of peptidases in PP degradation to determine whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. Dipeptidyl peptidase IV (DPPIV) and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogs. These findings suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogs resistant to cleavage by DPPIV and NEP might be useful in the development of PP as an anti-obesity pharmacotherapy. The degradation sites of pancreatic polypeptide (PP) by kidney and liver tissue preparations were investigated and used to create longer lasting anorectic analogs of PP.