The long-acting amylin/calcitonin receptor agonist ZP5461 suppresses food intake and body weight in male rats.
The long-acting amylin/calcitonin receptor agonist ZP5461 suppresses food intake and body weight in male rats.
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长效胰淀素/降钙素受体激动剂 ZP5461 可抑制雄性大鼠的食物摄入量和体重。
DOI：
10.1152/ajpregu.00337.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Mietlicki-Baase,ElizabethG
中科院分区：
文献类型：
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作者：
Stein,LaurenM;McGrath,LaurenE;Lhamo,Rinzin;Koch-Laskowski,Kieran;Fortin,SamanthaM;Skarbaliene,Jolanta;Baader-Pagler,Tamara;Just,Rasmus;Hayes,MatthewR;Mietlicki-Baase,ElizabethG
肽激素胰淀素减少食物摄入和体重，并且是治疗肥胖症的新型药物疗法的有吸引力的候选靶标。然而，天然胰淀素和胰淀素类似物如普兰林肽的短半衰期限制了这些化合物在促进持续负能量平衡中的潜在效用。在此，我们评价了新型长效胰淀素/降钙素受体激动剂ZP 5461降低大鼠摄食量和体重的能力，并检测了ZP 5461长期给药对后脑背侧迷走神经复合体（DVC）中降钙素受体（CTR）在能量平衡效应中的作用。急性剂量反应研究表明，全身ZP 5461（0.5-3 nmol/kg）可显著抑制普通饲料和高脂饲料（HFD）喂养大鼠的能量摄入和体重增加。当喂食HFD的大鼠接受ZP 5461（1-2 nmol/kg）长期全身给药时，该化合物最初导致能量摄入和体重增加减少，但未能持续抑制摄入和体重。使用病毒介导的DVC CTR敲低，确定慢性全身性ZP 5461促进摄入量和体重增量早期减少的能力部分由DVC CTR激活介导，表明DVC是ZP 5461的中心作用位点。未来的研究应讨论ZP 5461的其他给药方案，以确定替代剂量/给药频率是否会产生更持久的体重抑制。
The peptide hormone amylin reduces food intake and body weight and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds’ potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration. Acute dose-response studies indicate that systemic ZP5461 (0.5–3 nmol/kg) robustly suppresses energy intake and body weight gain in chow- and high-fat diet (HFD)-fed rats. When HFD-fed rats received chronic systemic administration of ZP5461 (1–2 nmol/kg), the compound initially produced reductions in energy intake and weight gain but failed to produce sustained suppression of intake and body weight. Using virally mediated knockdown of DVC CTRs, the ability of chronic systemic ZP5461 to promote early reductions in intake and body weight gain was determined to be mediated in part by activation of DVC CTRs, implicating the DVC as a central site of action for ZP5461. Future studies should address other dosing regimens of ZP5461 to determine whether an alternative dose/frequency of administration would produce more sustained body weight suppression.