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

Abstract

Obesity is a risk factor for stroke and is consequently one of the most common co-morbidities found in patients. There is therefore an identified need to model co-morbidities preclinically to allow better translation from bench to bedside. In preclinical studies, both diet-induced and genetically obese rodents have worse stroke outcome, characterised by increased ischaemic damage and an altered inflammatory response. However, clinical studies have reported an ‘obesity paradox’ in stroke, characterised by reduced mortality and morbidity in obese patients. We discuss the potential reasons why the preclinical and clinical studies may not agree, and review the mechanisms identified in preclinical studies through which obesity may affects stroke outcome. We suggest inflammation plays a central role in this relationship, as obesity features increases in inflammatory mediators such as C-reactive protein and interleukin-6, and chronic inflammation has been linked to worse stroke risk and outcome.

Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons

“…Similar findings have been shown in genetically obese T2D animals (reviewed in [11]). The ones employing more physiological and clinically relevant obese/T2D models (induced by high-fat diet (HFD)) have mostly focused on the acute outcome (infarct size and neurological impairment) after stroke and, in the cases with more long-term outcome measures, the increase in the stroke injury was likely a determinant factor for decreased neurological recovery (reviewed in [11]). At present, it is therefore undetermined whether T2D induced by a chronic obesogenic diet affects long-term stroke recovery and if so, whether this effect is related to the impairment of brain's self-repair mechanisms.…”

“…Experimental stroke studies using toxin-induced hyperglycemia have shown that, similar to clinical observations, the neurological recovery in hyperglycemic animals is significantly attenuated [9,10]. Similar findings have been shown in genetically obese T2D animals (reviewed in [11]). The ones employing more physiological and clinically relevant obese/T2D models (induced by high-fat diet (HFD)) have mostly focused on the acute outcome (infarct size and neurological impairment) after stroke and, in the cases with more long-term outcome measures, the increase in the stroke injury was likely a determinant factor for decreased neurological recovery (reviewed in [11]).…”

“…The effect of genetic, toxin-induced T2D, or short-term 'high fat, high sugar' diets to worsen brain injury and exacerbate neurological deficits after stroke has been reported by a number of preclinical studies [9][10][11]. In these studies, the difference in the severity of brain injury after stroke between normal and T2D animals not only complicates the clear-cut determination of whether T2D also influences post-acute neurological recovery, but also the understanding of the underlying mechanisms, since the initial differences in injury severity influences both these parameters [52].…”

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

“…Along with metabolic derangements, obesity is associated with significant and protracted increase in inflammatory markers, and as such it has been described as a low-grade chronic inflammatory state. 42 Low-grade inflammation and systemic oxidative stress have proven to be damaging for the endothelium, shifting it toward a prothrombotic state. Platelet reactivity, enhanced coagulation, and impaired fibrinolysis are other recognized mechanisms.…”

Caloric restriction stabilizes body weight and accelerates behavioral recovery in aged rats after focal ischemia

“…Moreover, other studies suggest that apart from molecular factors secreted in the setting of obesity and ischemic stroke, the integrity of the blood–brain barrier is affected in obese subjects. Thus, it was reported that at 4 and 24 h after the ischemic event, the obese mice have a significant blood–barrier breakdown characterized by an increased amount of endothelial vesicles, suggesting vascular damage (Haley & Lawrence, ). However, it is not clear which are the factors that modulate the blood–brain barrier damage.…”