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

Abstract

BackgroundObesity 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.MethodsMale C57BL/6 mice were maintained on 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-month diet) or 30 min (2-, 3-, 4- and 6-month diet). Ischaemic damage, blood–brain barrier (BBB) integrity, neutrophil number and chemokine expression in the brain were assessed at 24 h. Plasma chemokine levels (at 4 and 24 h) and neutrophil number in the liver (at 24 h) 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.ResultsMice 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-min (but not 20-min) occlusion of the MCA, obese mice had greater ischaemic brain damage. An increase 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-min 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.ConclusionsThe 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.

Total Western Diet Alters Mechanical and Thermal Sensitivity and Prolongs Hypersensitivity Following Complete Freund's Adjuvant in Mice

“…Although not examined in our experiment, the HFD has been shown to increase the extent of damage following ischemic injury in mice 22 and to increase immune cell entry into the central nervous system 4 . We hypothesize that the TWD led to a hyper-responsive immune system that enhanced the hypersensitivity and prolonged the recovery from inflammatory pain induction.…”

Obesity and stroke: Can we translate from rodents to patients?

“…57 Worse stroke outcome has also been confirmed in diet-induced models in which animals become obese due to being fed a high-fat diet. These detrimental effects of a high-fat diet have been observed in rat, 58,61,65,73,82,93 mouse 60,64,66,88 and gerbil 62,63,94 models of diet-induced obesity. A variety of models of cerebral ischaemia have also been used in these studies, including transient and permanent occlusion of the middle cerebral artery, common carotid artery ligation and exposure to a low-oxygen environment.…”

“…In mice, it has recently been shown that the negative impact of diet-induced obesity on stroke outcome in mice is dependent on how long the obese phenotype is present and the severity of the initial stroke insult (length of ischaemia). 60 It is also unclear whether the detrimental effects of obesity on outcome in these preclinical studies are permanent, or reversible with weight loss. …”

“…60 This enhanced microvascular damage in obese animals likely contributes to their worse ischaemic damage due to the neurotoxic effects of both BBB breakdown and haemorrhagic transformation. Perhaps owing to the important role of the BBB in brain ion and water homoeostasis, an increase cerebral oedema is seen in obese rodents.…”

“…90 In contrast, other studies have shown cytokine and chemokine expression levels are increased in ischaemic brain tissue of obese rats and mice. 58,60,75,76 This heightened central inflammatory response could be due to the increased damage in the obese rodents, although elevated expression of inflammatory mediators is observed as early as 2.5 h after reperfusion. 76 …”