|Institution:||University of Manchester|
|Keywords:||obesity; stroke; metabolomics; metabolism; blood-brain barrier|
|Full text PDF:||http://www.manchester.ac.uk/escholar/uk-ac-man-scw:217538|
Obesity is an independent risk factor for ischaemic stroke and may worsen stroke outcome. Therefore, the objective of this thesis was to identify potential interactions between obesity and stroke, with particular focus on inflammatory mechanisms.Ischaemic stroke was surgically induced in obese (ob/ob) and control (ob/-) mice by middle cerebral artery occlusion (MCAO). Outcome was worse in ob/ob mice, which showed rapid and severe ischaemic and vascular damage, characterised by blood vessel haemorrhage as early as 30 minutes post-stroke. The early vascular damage is likely an important driver of subsequent ischaemic damage by exacerbating inflammation in the brain. Assessment of systemic inflammation in ob/ob mice found that stroke had triggered a deregulated inflammatory response in the plasma, spleen, liver and bone marrow, and increased adipose tissue inflammation.Increased vascular damage was hypothesised to mediate the worse outcome found in obese rodents. The structural and inflammatory state of the vasculature was therefore assessed in ob/ob mice prior to and after stroke. Prior to stroke, increased vascular inflammation was found in ob/ob mice, though no differences in tight junction expression or structural alterations were noted. Stroke resulted in vascular damage that was similar on structural and molecular levels between genotypes, though ob/ob mice showed an increase in transcytosis in endothelial cells which may mediate their enhanced blood-brain barrier breakdown.Some studies have found obese patients have better outcome after stroke, perhaps because they are protected from detrimental post-stroke weight loss. The metabolic response to MCAO was therefore assessed, with ob/ob mice showing altered lipid metabolism post-stroke, such as increased fatty acid release from adipose tissue into the plasma. The potential role of fatty acid release in triggering adipose inflammation was also assessed in adipose tissue explants, though limited evidence for an inflammatory response to lipolysis was found.Overall, these findings suggest rapid and enhanced vascular damage may drive worse stroke outcome in ob/ob mice, as may their altered immunological and metabolic states.