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

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rosuvastatin 1 endocrinologydiseasesdrugs
metabolic syndrome 8 endocrinologydiseases
obesity 107 endocrinologydiseases

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potassium chloride 24898 arteries from obese animals show increased vasoconstriction in response to 5-hydroxtryptamine (5-HT), potassium chloride (KCl) and endothelin-1 (ET-1), and reduced vasodilation in response to acetylcholine.[83],[93],[119]
rosuvastatin 20739 suggesting the peripheral inflammatory response may contribute to damage in obesity.[86] Similarly, both rosuvastatin (a statin) and darglitazone (a PPAR-γ agonist) were shown to be anti-inflammatory and neuroprotective
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metabolic syndrome 3812 reduced efficacy of tPA.[16] Similar resistance to thrombolysis has been reported in patients with the metabolic syndrome ,[17],[18] of which obesity is a part. A potential explanation is that patients weighing over 100 kg
metabolic syndrome 4896 co-morbid diseases such as hypertension, vascular disease (e.g. atherosclerosis), diabetes, infection or metabolic syndrome /obesity. Several of these co-morbidities may co-exist in the same patient, and it is rare for a stroke
metabolic syndrome 5131 an otherwise healthy individual (Figure 1). Figure 1.Obesity develops alongside other aspects of the metabolic syndrome and leads to chronic ‘low grade inflammation’. Systemic inflammation is known to affect stroke outcome,
metabolic syndrome 5286 inflammation’. Systemic inflammation is known to affect stroke outcome, as are other aspects of the metabolic syndrome . CRP: C reactive protein; CCL2: chemokine (C-C motif) ligand 2; CXCL2: chemokine (C-X-C motif) ligand
metabolic syndrome 29712 being merely pro- or anti-inflammatory.Obesity and other co-morbiditiesObesity is a component of the metabolic syndrome , and so is often accompanied by hyperglycaemia, hypertension and dyslipidaemia in patients that may
metabolic syndrome 30439 in patients, but also in preclinical models of obesity that often develop different aspects of the metabolic syndrome dependent on their age, diet and genetic background (Table 1). For example, leptin-deficient ob/ob mice,
metabolic syndrome 30702 and mice fed a high fat diet all not only become obese, but eventually develop other aspects of the metabolic syndrome to some extent.[142],[143] Studies in obese rats have shown that presence of hypertension is critical
metabolic syndrome 34453 discussed, the resulting phenotype in both models is not solely increased adiposity, but more similar to metabolic syndrome found in patients. This is an accurate recapitulation of the clinical situation, as individual patients
obesity 766 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
obesity 1027 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
obesity 1133 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
obesity 1365 linked to worse stroke risk and outcome.Obesity as a stroke co-morbidityThe detrimental effects of obesity on overall health are well understood, including an increased risk of developing hypertension and cardiovascular
obesity 1690 classified as clinically obese (EUROASPIRE III survey),[2] we do not fully understand whether or how obesity affects stroke outcome. Stroke is already the leading cause of adult disability, accounting for 7% of
obesity 2092 will likely increase due to the population living longer. As well as an ageing population, worldwide obesity has more than doubled since 1980, and in 2014, over 600 million adults were classified as obese (World
obesity 2580 then further divided based on BMI into class 1 (30–34.9), class 2 (35–39.0) or class 3 (≥40) obesity . Several studies have identified that obesity is a risk factor for both ischaemic and haemorrhagic stroke
obesity 2626 1 (30–34.9), class 2 (35–39.0) or class 3 (≥40) obesity. Several studies have identified that obesity is a risk factor for both ischaemic and haemorrhagic stroke in several ethnic populations and in both
obesity 3176 diabetes and dyslipidaemia. However, even after adjustment for these potential co-founding factors, obesity has been found to be an independent risk factor for stroke.[5]Currently, the only treatment for stroke
obesity 3850 resistance to thrombolysis has been reported in patients with the metabolic syndrome,[17],[18] of which obesity is a part. A potential explanation is that patients weighing over 100 kg may be underdosed, as the
obesity 4915 as hypertension, vascular disease (e.g. atherosclerosis), diabetes, infection or metabolic syndrome/ obesity . Several of these co-morbidities may co-exist in the same patient, and it is rare for a stroke to occur
obesity 5931 disruption of pathways controlling lipid and glucose metabolism, however recent evidence has shown that obesity also has an inflammatory component (Figure 1). Measures of obesity, such as BMI, correlate with several
obesity 5998 however recent evidence has shown that obesity also has an inflammatory component (Figure 1). Measures of obesity , such as BMI, correlate with several markers of inflammation in patients. In particular, circulating
obesity 6229 C-reactive protein (CRP) and interleukin (IL)-6 have been shown repeatedly to correlate positively with obesity [24][25][26][27][28]–[29] in addition to tumour necrosis factor alpha (TNFα),[29] monocyte chemoattractant
obesity 6558 This positive correlation between makers of inflammation and adiposity has led to suggestions that obesity is an inflammatory condition. However, the profile of immune activation found in obesity is quite different
obesity 6647 suggestions that obesity is an inflammatory condition. However, the profile of immune activation found in obesity is quite different to that found in infection or injury, where the immune system is acutely activated
obesity 6787 in infection or injury, where the immune system is acutely activated to remove harmful stimuli. In obesity , the concentrations of proinflammatory markers are relatively low by comparison, but are maintained
obesity 6928 proinflammatory markers are relatively low by comparison, but are maintained over long periods. Consequently, obesity has been described as resulting in “low-grade chronic inflammation”. This peripheral inflammatory
obesity 7142 response is thought to originate within adipose tissue, which becomes dysfunctional and inflamed during obesity .[32] The important endocrine role of adipose tissue is highlighted by the growing family of adipose
obesity 7655 metabolism, blood pressure, insulin sensitivity and angiogenesis.[32],[33] The inflammation associated with obesity may lead to progressively increased stroke risk, since elevated concentrations of IL-6 and CRP in the
obesity 8109 for CRP, suggesting that inflammation is important in mediating the risk of stroke associated with obesity .[38]Stroke outcome in obese patients: The obesity paradoxDespite obesity being a risk factor for stroke,
obesity 8159 important in mediating the risk of stroke associated with obesity.[38]Stroke outcome in obese patients: The obesity paradoxDespite obesity being a risk factor for stroke, several studies have reported a protective effect
obesity 8182 of stroke associated with obesity.[38]Stroke outcome in obese patients: The obesity paradoxDespite obesity being a risk factor for stroke, several studies have reported a protective effect of obesity on stroke
obesity 8275 paradoxDespite obesity being a risk factor for stroke, several studies have reported a protective effect of obesity on stroke outcome in patients. In these studies, patients are grouped by BMI on admission, and the presence
obesity 9262 reduced short-term mortality.[40],[48],[50]However, not all studies have confirmed the existence of an obesity paradox in stroke. For example, Ryu et al. found no association between increased BMI and long-term
obesity 9573 strokes on admission, and so when initial stroke severity was adjusted for there was no evidence of an obesity paradox in their cohort.[52] In a study in patients receiving intravenous thrombolysis, body weight
obesity 10016 include deaths confirmed as occurring acutely due to the index stroke, there was no evidence of an obesity paradox.[53] There is therefore still a lack of consensus about the obesity paradox in the literature;
obesity 10092 there was no evidence of an obesity paradox.[53] There is therefore still a lack of consensus about the obesity paradox in the literature; whether it predicts a currently unclear biological phenomenon, or is instead
obesity 10485 Overall, the clinical studies investigating stroke outcome in obese patients have focused on whether obesity has a positive or negative effect on long-term morbidity and mortality. However, the actual mechanisms
obesity 10610 negative effect on long-term morbidity and mortality. However, the actual mechanisms through which obesity is proposed to have a beneficial or detrimental effect have undergone little to no investigation in
obesity 10863 rodentsIn contrast with the clinical outlook, there is clear consensus in preclinical studies that obesity worsens stroke outcome. This detrimental effect of obesity on outcome has primarily been demonstrated
obesity 10922 clear consensus in preclinical studies that obesity worsens stroke outcome. This detrimental effect of obesity on outcome has primarily been demonstrated in obese rodents undergoing experimental cerebral ischaemia.
obesity 11066 demonstrated in obese rodents undergoing experimental cerebral ischaemia. In both mouse and rat models of obesity , obese rodents suffer increased ischaemic brain damage and have worse behavioural outcomes in comparison
obesity 11280 with control animals (Table 1). This unfavourable effect was initially observed in genetic models of obesity , such as the ob/ob mouse,[57],[63],[78],[80],[84],[86][85]–[88]db/db mouse[74],[75],[77],[91],[92]
obesity 12071 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
obesity 12385 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
obesity 12602 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. Table 1.Summary
obesity 12874 and the co-morbidities which they assessed.StudySpecies, strainObesity modelIschaemia modelEffect of obesity on ischaemia outcomeCo-morbidities assessedBWGlu.Ins.Lip.BPHaley and Lawrence[57]Mouse, ob/obLeptin
obesity 17424 haemorrhagic transformation are all indicators of poor prognosis in patients.[95][96][97]–[98]Effects of obesity on neuroinflammation in experimental strokeThe chronic low-grade inflammation resulting from obesity
obesity 17525 obesity on neuroinflammation in experimental strokeThe chronic low-grade inflammation resulting from obesity may affect stroke outcome by modulating central nervous system (CNS) inflammation prior to stroke. Obese
obesity 18073 stimulation of afferent nerve fibres. However, the systemic elevation of inflammatory mediators in obesity is likely not great enough to cause an overt inflammatory response in the CNS. Instead, the low-level
obesity 18214 cause an overt inflammatory response in the CNS. Instead, the low-level systemic inflammation found in obesity may prime cells to subsequent inflammatory stimuli, for example leukocytes and platelets in the circulation.[86],[99]
obesity 18651 activation.[100][101][102][103]–[104] However, these responses could be due to dietary fats, rather than the resulting obesity . Increases in basal inflammation may therefore alter the reactivity of cells within the CNS to subsequent
obesity 19771 expression of inflammatory mediators is observed as early as 2.5 h after reperfusion.[76]Effects of obesity on peripheral inflammatory response to experimental strokeStroke triggers a peripheral immune response
obesity 20370 this process is thought to amplify the post-ischaemic inflammatory reaction and resulting damage. In obesity , the post-stroke peripheral immune response appears to be increased, as plasma IL-6, CCL2/MCP-1 and
obesity 20710 the damage in ob/ob mice, suggesting the peripheral inflammatory response may contribute to damage in obesity .[86] Similarly, both rosuvastatin (a statin) and darglitazone (a PPAR-γ agonist) were shown to be anti-inflammatory
obesity 21004 exacerbates microvascular disruption in experimental strokeEvidence from rodent studies suggests that obesity exacerbates inflammatory disruption of cerebral microvessels, worsening stroke outcome. This is seen
obesity 21945 high-fat fed MMP-9 knock out mice[64] suggesting a causative role of MMP-9 in the detrimental effects of obesity . MMP-9 is expressed by cerebral vessels after stroke in ob/ob mice,[80] but MMP-9 may also originate
obesity 22826 ICAM-1 expression, which may mediate neutrophil recruitment.[58],[75],[76] These data suggest that obesity exacerbates inflammatory processes converging at the brain microvasculature endothelium, resulting in
obesity 23108 unclear whether these effects are mediated by changes within or external to the vasculature. For example, obesity may result in changes to the vasculature that subsequently worsens the vascular response to stroke.
obesity 23774 (BMI ≥ 25 kg/m2).[116] Furthermore, in patients receiving intravenous thrombolysis after stroke, obesity had no effect on the development of haemorrhagic transformation.[117],[118] This is in contrast to genetically
obesity 26165 vascular resistance and impaired autoregulation may contribute to worsened stroke outcome or risk in obesity .The relationship between altered adipokines in obesity and strokePlasma levels of adiponectin are high
obesity 26220 contribute to worsened stroke outcome or risk in obesity.The relationship between altered adipokines in obesity and strokePlasma levels of adiponectin are high in healthy adults, but reduce in correlation with increasing
obesity 28420 obese mice where adiponectin levels are chronically decreased. In support, recent data demonstrate that obesity exacerbates experimental ischaemia by increasing apoptosis of adiponectin-expressing neurones.[61]The
obesity 28732 reporting seemingly conflicting conclusions. Since leptin circulates at levels proportional to body fat, obesity results in an increase in plasma leptin concentration. However, because these high concentrations are
obesity 28853 increase in plasma leptin concentration. However, because these high concentrations are sustained, obesity may result in desensitisation to central leptin signalling.[136] Using lean mice, Zhang et al.[137]
obesity 30222 increases HT risk.[140] Importantly, the pathological evolution of these conditions is intimately linked to obesity ,[141] so that disassociating the specific impact of obesity on health outcomes is difficult. This is
obesity 30282 these conditions is intimately linked to obesity,[141] so that disassociating the specific impact of obesity on health outcomes is difficult. This is the case in patients, but also in preclinical models of obesity
obesity 30387 obesity on health outcomes is difficult. This is the case in patients, but also in preclinical models of obesity that often develop different aspects of the metabolic syndrome dependent on their age, diet and genetic
obesity 30860 obese rats have shown that presence of hypertension is critical in whether the detrimental effect of obesity on stroke outcome is observed.[79],[83] In contrast, the relationship between obesity and a worsened
obesity 30946 detrimental effect of obesity on stroke outcome is observed.[79],[83] In contrast, the relationship between obesity and a worsened stroke outcome has been confirmed in mice without hypertension or hyperglycaemia.[60],[80],[86],[93]
obesity 31284 their causative pathologies are not present and developing. This means that although animal models of obesity mimic the situation in obese people, the possible contribution from other co-morbidities should be considered
obesity 31455 from other co-morbidities should be considered when attempting to study specifically the effects of obesity on stroke. This is especially important when considering effects of obesity on the cerebral microvasculature
obesity 31531 specifically the effects of obesity on stroke. This is especially important when considering effects of obesity on the cerebral microvasculature where the deleterious effects on stroke outcome of both diabetes and
obesity 31970 often also obese.Reconciling preclinical and clinical outlooksDespite the well-established link between obesity and stroke risk, several clinical studies have reported that obese and overweight stroke patients have
obesity 32212 morbidity. This is in stark contrast to the consensus of preclinical studies, which have clearly shown that obesity worsens stroke outcome in rodents. There are many potential reasons for this disparity, which will be
obesity 32549 studies.Common limitations of preclinical experimental studiesThe preclinical studies assessing the effects of obesity on stroke outcome are all experimental, and have several limitations in common. Whereas the clinical
obesity 32940 ischaemic lesion within 48 h of reperfusion. This focus on short-term outcomes may explain why no obesity paradox is found in preclinical studies. For example, a hypothesised reason that obesity is protective
obesity 33029 explain why no obesity paradox is found in preclinical studies. For example, a hypothesised reason that obesity is protective in stroke patients is that the metabolic reserves present in obesity protects against
obesity 33112 hypothesised reason that obesity is protective in stroke patients is that the metabolic reserves present in obesity protects against post-stroke weight loss, and associated muscle wasting.[145] The metabolic consequences
obesity 33322 consequences of stroke have been poorly studied pre-clinically in general, and even less so in the context of obesity . In preclinical studies, stroke is usually surgically induced in obese mice, rather than waiting for
obesity 33479 surgically induced in obese mice, rather than waiting for spontaneous strokes to occur. Therefore, if the obesity paradox is primarily due to the effects of obesity on risk, for example increasing the risk of a stroke
obesity 33530 spontaneous strokes to occur. Therefore, if the obesity paradox is primarily due to the effects of obesity on risk, for example increasing the risk of a stroke earlier in life, then this would not be detectable
obesity 34122 model human stroke. This question has been discussed in detail elsewhere.[146],[147]Animal models of obesity and their co-morbiditiesWorse stroke outcome has been reported in both genetically obese and diet-induced
obesity 34892 co-morbidities, it becomes difficult to attribute the worse outcome in rodent models as being solely due to obesity . This is in contrast to clinical studies that can quantify the specific contribution of obesity to stroke
obesity 34988 to obesity. This is in contrast to clinical studies that can quantify the specific contribution of obesity to stroke outcome by applying multivariate statistics to large, heterogeneous patient populations. By
obesity 35602 clinical situation found in obese patients, both have other drawbacks. Monogenic mutations leading to obesity are actually very rare in the general population and leptin has other immunological roles beyond regulation
obesity 35764 leptin has other immunological roles beyond regulation of energy balance.[148],[149] In diet-induced obesity , the constitution of the diet (principally the macronutrient ratio of fats, protein and carbohydrates)
obesity 36049 extra variable to consider, as effects on outcome may be due to the diet per se, rather the resulting obesity . Preclinical studies also use animals that are more homogenously and robustly obese than the patient
obesity 36240 than the patient population. Although this homogeneity makes interpretation of the contribution of obesity easier in experimental studies, it ignores the potentially protective effects of mild obesity (e.g.
obesity 36334 contribution of obesity easier in experimental studies, it ignores the potentially protective effects of mild obesity (e.g. overweight). For example, mice fed a high-fat diet for 4 months show an average body weight increase
obesity 36633 translates to an increase in ‘mouse BMI’ to 32–40. In both mice and rats, the harmful effects of obesity on stroke outcome are not observed until a threshold level of obesity is obtained.[60],[73]Common limitations
obesity 36703 rats, the harmful effects of obesity on stroke outcome are not observed until a threshold level of obesity is obtained.[60],[73]Common limitations of clinical observational studiesThe clinical studies assessing
obesity 36829 obtained.[60],[73]Common limitations of clinical observational studiesThe clinical studies assessing the impact of obesity on stroke outcome are almost universally observational – experimental studies in this setting are
obesity 37024 setting are not possible as they would require purposefully exposing patients to either stroke and obesity . For similar reasons, observational studies are limited in their potential outcomes as non-invasive
obesity 37626 observational studies is their potential for selection bias. A typical epidemiological study assessing how obesity affects stroke outcome will include all patients in their cohort that present with ischaemic stroke
obesity 38038 relationships or associations between effects (factors that can affect the risk of stroke), for example between obesity and age. For this reason, the average age of patients in the obese groups is lower than in the non-obese
obesity 38194 patients in the obese groups is lower than in the non-obese groups of several studies reporting on the obesity paradox, with age often decreasing inversely with BMI and reaching a difference of 10 years in the most
obesity 38829 the presence of stroke will also create non-causal relationship between these unmeasured effects and obesity due to collider-stratification bias. As we cannot statistically adjust or account for the presence of
obesity 39001 adjust or account for the presence of unmeasured effects, they can distort the relationship between obesity and stroke outcome. This confounding of the stroke-mortality relationship by unmeasured confounding
obesity 39197 confounding effects has been hypothesised to account for all of,[151] or at least part of,[152] the obesity paradox.The existing clinical studies have primarily used BMI as a measure of obesity, but BMI may not
obesity 39283 of,[152] the obesity paradox.The existing clinical studies have primarily used BMI as a measure of obesity , but BMI may not always be the best indicator of adiposity. This is primarily because BMI does not discriminate
obesity 39444 adiposity. This is primarily because BMI does not discriminate between lean body mass and fat mass, and obesity is associated with an increase in both lean and fat mass. Other measures of obesity may more accurately
obesity 39528 and fat mass, and obesity is associated with an increase in both lean and fat mass. Other measures of obesity may more accurately reflect harmful adiposity, for example visceral/abdominal obesity rather than BMI
obesity 39614 Other measures of obesity may more accurately reflect harmful adiposity, for example visceral/abdominal obesity rather than BMI is more strongly correlated with metabolic health.[153],[154] In support of this, obesity
obesity 39720 obesity rather than BMI is more strongly correlated with metabolic health.[153],[154] In support of this, obesity has a beneficial effect on vascular disease survival in obese diabetic patients when obesity is classified
obesity 39813 this, obesity has a beneficial effect on vascular disease survival in obese diabetic patients when obesity is classified by BMI, but not when classified by waist circumference.[155] Furthermore, people with
obesity 40460 indicator of lean body mass than adiposity.[157]ConclusionPreclinical research has clearly shown that obesity worsens stroke outcome in rodents, suggesting a central role of pathological changes in the cerebrovasculature,
obesity 40672 cerebrovasculature, including vascular inflammation and remodelling. In comparison, it is still unclear whether obesity worsens outcome in patients, and many preclinical findings cannot be replicated in the clinic. Future
obesity 41049 example, studies assessing longer term functional outcomes in obese rodents could give insights into the obesity paradox in patients.In this approach, preclinical studies should aim to make findings, which are verifiable
obesity 41407 preclinical and clinical outlooks, several key mechanisms that may mediate the interaction between stroke and obesity have been identified (Figure 2), though the potential interactions not fully discussed here are extensive.
obesity 41587 fully discussed here are extensive. This complexity is due to the wide-ranging effects of stroke and obesity on physiology, spanning cardiovascular, neurological, immunological and metabolic systems. Another complication
obesity 41758 immunological and metabolic systems. Another complication for both preclinical and clinical research is that obesity commonly occurs with other conditions such as hypertension and diabetes. Figure 2.Summary of potential
obesity 41888 other conditions such as hypertension and diabetes. Figure 2.Summary of potential mechanism by which obesity may affect stroke outcome. The effects of obesity on stroke outcome appear to converge at the cerebral
obesity 41938 diabetes. Figure 2.Summary of potential mechanism by which obesity may affect stroke outcome. The effects of obesity on stroke outcome appear to converge at the cerebral vasculature and the blood–brain barrier, with
obesity 42415 obese animals and patients. This figure is not exhaustive, as there are many hypothetical ways in which obesity may affect stroke, which have not yet been studied. BBB: blood-brain barrier; CRP: C reactive protein;
obesity 43051 obese rodents. Furthermore, there is a clinically established role of inflammation in both stroke and obesity . Further work is therefore required to reconcile the preclinical and clinical outlooks and allow identification

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