Phosphodiesterase 5 Inhibitor Improves Insulin Sensitivity by Regulating Adipose Tissue Macrophage Polarization in Diet-Induced Obese Mice.

IF 6.8 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Dan-Gyeong Song, Seongwon Pak, Dae-Chul Shin, Shindy Soedono, Kae Won Cho, Yejin Park, Subin Moon, Sooyeon Jang, Saeha Kim, Sang-Won Han, Keunwook Lee, Jong-Hee Sohn, Chan Hee Lee
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引用次数: 0

Abstract

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.

磷酸二酯酶5抑制剂通过调节饮食诱导肥胖小鼠脂肪组织巨噬细胞极化改善胰岛素敏感性。
背景:肥胖是一个快速增长的全球健康问题,它与葡萄糖和胰岛素抵抗有关。磷酸二酯酶5型(PDE5)抑制剂(PDE5i)以其增强血液流动和血管稳定性的能力而闻名,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在减轻肥胖和代谢性疾病中的作用的研究仍不清楚。因此,我们研究了PDE5i对饮食诱导的肥胖小鼠肥胖和代谢紊乱的影响及其潜在机制。方法:将PDE5i给予高脂饮食(HFD)喂养的C57BL/6J小鼠6 ~ 7周。每周测量体重和食物摄入量,在PDE5i给药期间评估基线代谢率、体力活动、葡萄糖和胰岛素耐量试验。采用流式细胞术对大鼠性腺白色脂肪组织(gWAT)中的巨噬细胞和t细胞进行分析。通过免疫染色和活体显像分析gWAT血管稳定性和血流量。采用RAW264.7细胞和骨髓源性巨噬细胞检测PDE5i的免疫调节作用。结果:在饲喂hfd的小鼠中,PDE5i显著增强了gWAT的全身胰岛素敏感性和AKT磷酸化。PDE5i降低肥胖小鼠gWAT巨噬细胞M1/M2比值。这些现象与流向gWAT的血流量增加有关。体外实验表明,PDE5i抑制脂多糖诱导的促炎细胞因子的产生,增加M2极化相关基因的mRNA表达。结论:PDE5i在调节脂肪组织炎症中发挥作用,有望成为促进代谢的治疗药物。
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来源期刊
Diabetes & Metabolism Journal
Diabetes & Metabolism Journal Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
10.40
自引率
6.80%
发文量
92
审稿时长
52 weeks
期刊介绍: The aims of the Diabetes & Metabolism Journal are to contribute to the cure of and education about diabetes mellitus, and the advancement of diabetology through the sharing of scientific information on the latest developments in diabetology among members of the Korean Diabetes Association and other international societies. The Journal publishes articles on basic and clinical studies, focusing on areas such as metabolism, epidemiology, pathogenesis, complications, and treatments relevant to diabetes mellitus. It also publishes articles covering obesity and cardiovascular disease. Articles on translational research and timely issues including ubiquitous care or new technology in the management of diabetes and metabolic disorders are welcome. In addition, genome research, meta-analysis, and randomized controlled studies are welcome for publication. The editorial board invites articles from international research or clinical study groups. Publication is determined by the editors and peer reviewers, who are experts in their specific fields of diabetology.
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