Microvascular insulin resistance in skeletal muscle and brain occurs early in the development of juvenile obesity in pigs

Background: Impaired microvascular insulin signaling may develop prior to overt indices of microvascular endothelial dysfunction and represent an early pathological feature of adolescent obesity. Using a translational porcine model of juvenile obesity, we tested the hypotheses that in the early stages of obesity development, impaired insulin signaling manifests in skeletal muscle (triceps), brain (prefrontal cortex) and corresponding vasculatures, and that depressed insulin-induced vasodilation is reversible with acute inhibition of protein kinase C beta (PKCβ). Methods and Results: Juvenile Ossabaw miniature swine (3.5-months of age) were divided into two groups: lean control (n=6) and obese (n=6). Obesity was induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 10-weeks. Juvenile obesity was characterized by excess body mass, hyperglycemia, physical inactivity (accelerometer) and marked lipid accumulation in the skeletal muscle, with no evidence of overt atherosclerotic lesions in athero-prone regions such as the abdominal aorta. Endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) vasomotor responses in the brachial and carotid arteries (wire myography) as well as in the skeletal muscle resistance and 2A pial arterioles (pressure myography) were unaltered, but insulin-induced microvascular vasodilation was impaired in the obese group. Blunted insulin-stimulated vasodilation, which was reversed with acute PKCβ inhibition (LY333-351), occurred alongside decreased tissue perfusion as well as reduced insulin-stimulated Akt signaling in the prefrontal cortex, but not the triceps. Conclusions: In the early stages of juvenile obesity development, the microvasculature and prefrontal cortex exhibit impaired insulin signaling. Such adaptations may underscore vascular and neurological derangements associated with juvenile obesity.

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