Prolonged diet-induced obesity in mice modifies the inflammatory response and leads to worse outcome after stroke

Background: Obesity increases the risk for ischaemic stroke and is associated with worse outcome clinically and experimentally. Most experimental studies have used genetic models of obesity. Here a more clinically-relevant model, diet-induced obesity, was used to study the impact of obesity over time on the outcome and inflammatory response after stroke. Methods: Male C57BL/6 mice were maintained on either a high-fat (60%-fat) or control (12%-fat) diet for 2, 3, 4 and 6 months when experimental stroke was induced by transient occlusion of the middle cerebral artery (MCAo) for either 20 (6 months diet) or 30 minutes (2, 3, 4 and 6 months diet). Ischaemic damage, blood-brain barrier (BBB) integrity, neutrophil number and chemokine expression in the brain were assessed at 24 hours. Plasma chemokine levels (at 4 and 24 hours) and neutrophil number in the liver (at 24 hours) were measured. Physiological parameters (body weight and blood glucose) were measured in naïve control and high-fat fed mice at all time points and blood pressure at 3 and 6 months. Blood cell counts were also assessed in naïve 6-month control and high-fat fed mice. Results: Mice fed a high-fat diet for 6 months had greater body weight, blood glucose and white and red blood cell count but no change in systolic blood pressure. After 4 and 6 months of high-fat feeding, and in the latter group with a 30-minute (but not 20- minute) occlusion of the MCA, obese mice had greater ischaemic brain damage. Anincrease in blood-brain barrier permeability, chemokine expression (CXCL-1 and CCL3), neutrophil number and microglia/macrophage cells was observed in the brains of 6-month high-fat fed mice after 30 minutes MCAo. In response to stroke, chemokine (CXCL-1) expression in the plasma and liver was significantly different in obese mice (6-month high-fat fed), and a greater number of neutrophils were detected in the liver of control but not obese mice. Conclusions: The detrimental effects of diet-induced obesity on stroke were therefore dependent on the severity of obesity and length of ischaemic challenge. The altered inflammatory response in obese mice may play a key role in its negative impact on stroke.