Endothelial oxidative stress and vascular inflammation induce microvascular insulin resistance which 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 an euglycemic insulin clamp, in conjunction with contrast enhanced ultrasound, in adult male rats after 2 weeks of high-fat diet feeding with either access to running wheel (exercise), liraglutide (200 mg/kg subcutaneously twice daily), or the combination of both. Rats exhibited increased visceral adiposity and blunted microvascular responses (microvascular blood volume, flow velocity, and total flow) and metabolic insulin actions (glucose infusion rates). 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 oxidative stress in the muscle, attenuated blood vessel inflammation and improved endothelial function, along with increased nucleus translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and phosphorylation of AMP-activated protein kinase (AMPK) and nitric oxide synthase (eNOS) in endothelial cells. 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 microvascular and metabolic insulin resistance and associated complications during the development of obesity.


J.Liu: None. K.W.Aylor: None. Z.Liu: None.


National Institutes of Health (R01DK125330), (R01DK1124344 to Z.L.)

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