Cuenco Joyceline, Minnion James, Tan Tricia, Scott Rebecca, Germain Natacha, Ling Yiin, Chen Rong, Ghatei Mohammad, Bloom Stephen
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2AZ, United Kingdom.
Department of Endocrinology, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne 42100, France.
Endocrinology. 2017 Jun 1;158(6):1755-1765. doi: 10.1210/en.2016-1827.
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.
胰多肽（PP）是一种肠道激素，作用于Y4受体以降低食欲。肥胖人群餐后PP的增加减少，并且对外源性PP的厌食作用仍保持完全敏感。PP作为抗肥胖治疗方法的效用受到其短循环半衰期的限制。深入了解PP降解的机制可能有助于长效PP类似物的设计。我们研究了肽酶在PP降解中的作用，以确定抑制这些酶是否能提高PP在体内的血浆水平和生物活性。发现二肽基肽酶IV（DPPIV）和中性内肽酶（NEP）是两种可切割PP的肽酶。限制这两种肽酶的作用可改善PP和基于PP的类似物在体内的厌食作用。这些发现表明，使用特异性抑制剂抑制PP的降解和/或设计对DPPIV和NEP切割具有抗性的类似物，可能有助于将PP开发为抗肥胖药物疗法。
