Inflammation-induced vascular insulin resistance is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise and glucagon-like peptide 1 (GLP-1) receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development, we performed a euglycemic insulin clamp in adult male rats after 2 weeks of high-fat diet feeding with either access to running wheel (exercise), liraglutide, or both. Rats exhibited increased visceral adiposity and blunted microvascular and metabolic insulin responses. Exercise and liraglutide alone each improved muscle insulin sensitivity but their combination fully restored insulin-mediated glucose infusion rates. The combined exercise and liraglutide intervention enhanced insulin-mediated muscle microvascular perfusion, reduced perivascular macrophage accumulation and superoxide production in the muscle, attenuated blood vessel inflammation and improved endothelial function, along with increased endothelial nucleus translocation of NRF2 and increased endothelial AMPK phosphorylation. We conclude that exercise and liraglutide synergistically enhance the metabolic actions of insulin and reduce vascular oxidative stress and inflammation in the early stage of obesity development. Our data suggest that early combination use of exercise and GLP-1 receptor agonism might be an effective strategy in preventing vascular and metabolic insulin resistance and associated complications during the development of obesity.

中文翻译：

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利拉鲁肽和运动可协同减轻血管炎症并增强早期饮食引起的肥胖的代谢胰岛素作用


炎症引起的血管胰岛素抵抗是饮食引起的肥胖的早期事件，并导致代谢性胰岛素抵抗。为了检查运动和胰高血糖素样肽 1 (GLP-1) 受体激动剂单独或组合是否能在肥胖发展过程中调节血管和代谢胰岛素作用，我们在 2 周的高脂饮食后对成年雄性大鼠进行了正常血糖胰岛素钳夹试验。节食喂养，同时使用跑轮（运动）、利拉鲁肽或两者。大鼠表现出内脏肥胖增加、微血管和代谢胰岛素反应减弱。单独运动和利拉鲁肽均可改善肌肉胰岛素敏感性，但它们的组合可完全恢复胰岛素介导的葡萄糖输注率。运动和利拉鲁肽联合干预增强了胰岛素介导的肌肉微血管灌注，减少了血管周围巨噬细胞的积累和肌肉中超氧化物的产生，减轻了血管炎症并改善了内皮功能，同时增加了 NRF2 的内皮核易位和增加了内皮 AMPK 磷酸化。我们的结论是，运动和利拉鲁肽协同增强胰岛素的代谢作用，减少肥胖发展早期的血管氧化应激和炎症。我们的数据表明，早期联合使用运动和 GLP-1 受体激动剂可能是预防肥胖发展过程中血管和代谢胰岛素抵抗及相关并发症的有效策略。