Background: Obesity is a rapidly increasing global health issue, which is associated with glucose and insulin resistance. Phosphodiesterase type 5 (PDE5) inhibitors (PDE5i) are known for their ability to enhance blood flow and vascular stability and are widely used to treat conditions such as erectile dysfunction, pulmonary hypertension, heart failure, and cancer. However, studies investigating the role of PDE5i in alleviating obesity and metabolic diseases remains unclear. Therefore, we investigated the effects of PDE5i on obesity and metabolic disorders in diet-induced obese mice and its underlying mechanisms.

Methods: PDE5i was administered to high-fat diet (HFD)-fed C57BL/6J mice for 6 to 7 weeks. Body weight and food intake were measured weekly, and baseline metabolic rates, physical activity, and glucose and insulin tolerance tests were assessed during PDE5i administration. Macrophages and T-cells in the gonadal white adipose tissue (gWAT) were analyzed by flow cytometry. Vascular stability and blood flow in gWAT were analyzed via immunostaining and in vivo live imaging. RAW264.7 cells and bone marrow-derived macrophages were used to determine immunoregulatory effects of PDE5i.

Results: In HFD-fed mice, PDE5i administration significantly enhanced systemic insulin sensitivity and AKT phosphorylation in gWAT. PDE5i reduced the M1/M2 ratio of gWAT macrophages of obese mice. These phenomena were associated with enhanced blood flow to the gWAT. In vitro experiments revealed that PDE5i suppressed lipopolysaccharide-induced proinflammatory cytokine production and increased the mRNA expression of genes associated with M2 polarization.

Conclusion: PDE5i plays a role in regulating adipose tissue inflammation and thus holds promise as a therapeutic agent for metabolic enhancement.

Keywords: Adipose tissue; Insulin resistance; Macrophages; Obesity; Phosphodiesterase 5 inhibitors.

背景：肥胖是一个迅速增长的全球健康问题，与血糖和胰岛素抵抗有关。磷酸二酯酶5（PDE5）抑制剂（PDE5i）因其增强血液流动和血管稳定的能力而闻名，并被广泛用于治疗勃起功能障碍、肺动脉高压、心力衰竭和癌症等疾病。然而，关于PDE5i在缓解肥胖和代谢性疾病中的作用的研究尚不清楚。因此，我们研究了PDE5i对高脂饮食诱导的肥胖小鼠的肥胖和代谢紊乱的影响及其潜在机制。

方法：向喂食高脂肪饮食（HFD）的小鼠C57BL/6J连续给药PDE5i 6至7周。每周测量体重和食物摄入量，并在给药期间评估基础代谢率、身体活动以及葡萄糖和胰岛素耐受性测试。通过流式细胞术分析腹股沟白色脂肪组织（gWAT）中的巨噬细胞和T细胞。使用免疫染色和体内活体成像技术分析gWAT的血管稳定性和血流情况。利用RAW264.7细胞及骨髓来源的巨噬细胞确定PDE5i的免疫调节效应。

结果：在喂食HFD的小鼠中，PDE5i给药显著增强了全身胰岛素敏感性，并增加了gWAT中的AKT磷酸化。PDE5i降低了肥胖小鼠gWAT巨噬细胞M1/M2比率。这些现象与gWAT血流增加有关联。体外实验显示，PDE5i抑制了脂多糖诱导的促炎细胞因子产生，并提高了与M2极化相关的基因mRNA表达。

结论：PDE5i在调节脂肪组织炎症中起作用，因此作为代谢增强治疗剂具有潜力。

关键词：脂肪组织；胰岛素抵抗；巨噬细胞；肥胖症；磷酸二酯酶5抑制剂。