肥胖是胰腺导管腺癌（PDAC）的一个危险因素，这是一种预防策略有限的致命疾病。减少肥胖的生活方式干预是预防肥胖相关 PDAC 的潜在方法。在这里，我们研究了通过体力活动 (PA) 和/或饮食改变来减少肥胖是否可以减少人类炎症并预防小鼠中与肥胖相关的 PDAC。对受试者（超重和肥胖）PA 干预前后循环炎症相关细胞因子的比较显示，PA 降低了全身炎症细胞因子。具有胰腺特异性诱导型 KrasG12D 表达的小鼠在肥胖相关癌症发生期间和之后接受 PA 和/或饮食干预。在同时存在饮食诱导肥胖 (DIO) 和 KrasG12D 表达的小鼠中，PA 干预导致体重增加降低、抑制全身炎症、延缓肿瘤进展并减少脂肪组织中的促炎信号。然而，当肥胖先于胰腺 KrasG12D 表达时，这些益处并不那么明显。在基因工程小鼠模型中，将 PA 与饮食诱导减肥 (DI-WL) 相结合可延缓肥胖相关的 PDAC 进展，但无论肥胖状况如何，单独使用 PA 或与 DI-WL 或化疗相结合均不能阻止原位 PDAC 模型中 PDAC 肿瘤的生长。 PA 导致脂肪组织中 IL-15ra 的上调。 IL-15 的脂肪特异性过度表达会减缓 PDAC 的生长，但仅限于非肥胖小鼠。总体而言，我们的研究表明，单独使用 PA 或与 DI-WL 联合使用可以减少炎症并延缓与肥胖相关的 PDAC 的发生或进展。预防或控制肥胖的生活方式干预措施或针对减肥相关分子途径的疗法可以预防 PDAC 的进展。

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity (DIO) and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased pro-inflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to upregulation of IL-15ra in adipose tissue. Adipose-specific overexpression of IL-15 slowed PDAC growth but only in non-obese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC.