对抗肥胖及其相关代谢紊乱的干预措施可能会降低子宫内膜癌 (EC) 的发病率并改善预后。减肥的潜在选择包括药物治疗干预，例如替泽帕肽、一种双重作用的胰高血糖素样肽 1 (GLP-1) 和胃抑制性多肽 (GIP) 受体激动剂。鉴于此，我们在子宫内膜样 EC 的临床前小鼠模型中探索了替西帕肽的抗肥胖和抗肿瘤作用。从 4 周龄开始，Lkb1fl/flp53fl/fl 小鼠分别接受低脂饮食和高脂饮食喂养。 -脂肪饮食产生瘦或肥胖表型。诱导 EC 九周后，肥胖和瘦小鼠被随机分配接受替泽帕肽治疗 4 周。评估了体重和肿瘤重量、肿瘤转录组和代谢组图谱以及血清代谢标志物和趋化因子。在替泽帕肽治疗 2 周后，肥胖小鼠和瘦小鼠的体重都开始减轻，最终肥胖小鼠和瘦小鼠的体重显着减轻了 20.1%，瘦小鼠为 16.8%。替泽帕肽改善了肥胖引起的血清脂联素、瘦素、GIP 和 C 反应蛋白水平。此外，相对于载体，替泽帕肽能有效减少肥胖和瘦小鼠的肿瘤生长，抑制肥胖小鼠肿瘤中的 ErbB 信号传导和糖酵解/糖异生，并增加瘦小鼠肿瘤中的 O-连接糖基化生物合成和磷脂酶 D 信号传导。通过对 EC 肿瘤中代谢和免疫途径的影响来影响小鼠体重和肿瘤生长，而肥胖和瘦小鼠之间存在差异。这种新颖的减肥疗法值得进一步评估，作为 EC 管理的创新策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC.Starting at 4 weeks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed.Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice.Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.