Regular ArticleDiet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke
Introduction
Metabolic syndrome, described as obesity, insulin resistance, impaired glucose tolerance, hyperinsulinemia, dyslipidemia and hypertension (Reaven, 1988), increases an individual's risk of developing type 2 diabetes (Festa, 2000, Klein, 2002); the incidence of which is increasing worldwide (Bagust, 2002, Mokdad, 2003). Patients with type 2 diabetes are at increased risk for developing cardiovascular disease (Grundy et al., 1999). Importantly, type 2 diabetes increases the risk of stroke, and 70% of new stroke patients have diabetes or prediabetes (Kernan and Inzucchi, 2004).
Stroke is the third most common cause of death in the U.S and the leading cause of long-term disability (Rosamond et al., 2008). Studies suggest that the outcome of an ischemic stroke is directly affected by the structure and function of the cerebral vasculature. For instance, the large infarcts observed in stroke-prone spontaneously hypertensive rats (SHRSP) appear to be due, at least in part, to a reduced middle cerebral artery (MCA) lumen diameter (Coyle and Jokelainen, 1983). Few studies have characterized the effects of diabetes or obesity on cerebral vessels. One study using Goto–Kakizaki type 2 diabetic (GK) rats showed that the wall/lumen ratio and vessel collagen deposition were increased in diabetic rats compared to control (Harris et al., 2005). A recent study showed that obese Zucker rats have a reduced MCA lumen diameter and increased myogenic tone (Osmond et al., 2009). The obese Zucker rats are morbidly obese and therefore are not particularly reflective of the human population. No studies have investigated the effects of purely diet-induced obesity on the cerebral vasculature in a rat strain that has not been genetically modified. It is important to note that one cannot extrapolate the findings in the peripheral vasculature to the cerebral vessels. The larger cerebral arteries have been shown to contribute considerably to the total vascular resistance and the control of cerebral blood flow (Harper et al., 1984), making the study of their structure and function pertinent to the pathogenesis of cerebral ischemia.
To facilitate the study of the effects of diet-induced obesity several animal models have been described (Carroll, 1996, Hall, 1998). In the model developed by Levin et al. (1983), rats begin consuming a HF diet as adults and 50% become obese and hypertensive. This model mimics the effects of human obesity (Dobrian et al., 2000); renin–angiotensin system activation (Hall, 1994), increased leptin (Hirose et al., 1998), reduced growth hormone secretion (Kopelman et al., 1985) and increased oxidative stress (Van Gaal et al., 1995). While this model mimics the Western diet, it does not allow for investigation of the effect of obesity beginning in childhood on the adult cardiovascular system. This is an important clinical question as the incidence of childhood obesity has increased by more than 100% in the past 30 years (Rocchini, 2002) and longitudinal studies show childhood obesity is a risk factor for adult obesity (Kvaavik, 2003, Whitaker, 1997). To address this, we developed a model of obesity, where the rats begin consuming a HF diet at the earliest possible age of 3 weeks and continue into adulthood. Unlike the adult onset obesity model, almost 100% of the rats receiving the HF diet become obese and hypertensive and have elevated fasting blood glucose and plasma insulin (Smith, 2006, Zhou, 2005). Our goal was to assess the effects of diet-induced obesity on the cardiovascular system. We hypothesized that these rats would have larger ischemic cerebral infarcts than control rats and that their MCAs would have smaller lumen and outer diameters. We also proposed that the vessels from the obese rats would be stiffer as a result of alterations in collagen deposition and MMP activity.
Section snippets
Animals
Three-week-old male Sprague Dawley rats were obtained from Harlan (Indianapolis IN). Rats were maintained on a 12-hour light/dark cycle, housed two per cage and allowed access to food and water ad libitum. These studies were approved by the Institutional Animal Care and Use committee and were carried out in accordance with the National Institutes of Health guide of the care and use of laboratory animals. Rats were fed the HF diet (36% fat; 15.2% saturated, 20.8% unsaturated, 0.4% sodium, and
Cerebral infarct size
The obese rats were significantly heavier than the control rats (390.4 ± 7.7 vs 325.6 ± 9.1 g obese vs control p < 0.01). Cerebral ischemia was induced by MCAO, after 24 h of ischemia the cerebral infarct was significantly larger in the obese rats than control (Fig. 1). Systolic blood pressure was increased in the obese rats compared to control (161 ± 2 vs 137 ± 2 mm Hg obese vs control p < 0.05). We have previously reported that fasting blood glucose and plasma insulin levels are increased in this model
Discussion
There are three novel findings from these studies. Firstly we found that diet-induced obesity increases the damage caused by a permanent ischemic stroke. Secondly, the structure of the MCA, the vessel most commonly occluded in humans, is altered in obese rats in a manner that would impede blood flow. Lastly, we have shown that MMP activity and expression is altered in the obese rats and that this increases collagen I deposition.
To the best of our knowledge this is the first study to document an
Acknowledgments
This work was supported by the National Institutes for Health Grants DK074385 and NS054688 (AE). The American Diabetes Association (ADA) (7-07-RA-28; AMD), the ADA Amaranth Diabetes Fund, American Heart Association (0840122N; AMD) and Philip Morris USA Inc and Philip Morris International (AE) also supported this work.
References (38)
Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats
Microvasc. Res.
(2007)- et al.
Arachidonic acid induces augmented vasoconstriction via cyclooxygenase 1 in the aorta from rats fed a high-fat diet
Prostaglandins. Leukot. Essent. Fatty. Acids.
(2006) Gender differences of renal CYP-derived eicosanoid synthesis in rats fed a high-fat diet
Am. J. Hypertens.
(2005)The projected health care burden of Type 2 diabetes in the UK from 2000 to 2060
Diabet. Med.
(2002)- et al.
Remodeling of cerebral arterioles in chronic hypertension
Hypertension
(1989) Different involvement of extracellular matrix components in small and large arteries during chronic NO synthase inhibition
Hypertension
(2005)Hypertension, cardiac hypertrophy, and neurohumoral activity in a new animal model of obesity
Am. J. Physiol.
(1996)Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator
Stroke
(2000)Effects of ischemia and myogenic activity on active and passive mechanical properties of rat cerebral arteries
Am. J. Physiol. Heart Circ. Physiol.
(2002)- et al.
Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats
Stroke
(1983)
Development of hypertension in a rat model of diet-induced obesity
Hypertension
Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model of type 2 Diabetes
BMC. Neurol.
Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS)
Circulation
Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association
Circulation
Louis K. Dahl Memorial Lecture. Renal and cardiovascular mechanisms of hypertension in obesity
Hypertension
Abnormal kidney function as a cause and a consequence of obesity hypertension
Clin. Exp. Pharmacol. Physiol.
Arterial and microvascular contributions to cerebral cortical autoregulation in rats
Am. J. Physiol.
Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: role of endothelin-1
Diabetes
The obese gene product, leptin: possible role in obesity-related hypertension in adolescents
J. Hypertens.
Cited by (65)
Clarifying the effects of diabetes on the cerebral circulation: Implications for stroke recovery and beyond
2021, Brain Research BulletinDietary fructose as a model to explore the influence of peripheral metabolism on brain function and plasticity
2021, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Diet-induced metabolic disorders pose a risk for incidence of post-stroke depression [93], and exacerbate damage caused by ischemic stroke in cerebral vessels [94]. These events result in an increase in BBB permeability and pro-inflammatory response that may exacerbate infarct volume [95,96]. The period of fructose exposure seems a critical factor for the involvement of systemic metabolism and subsequent effects on brain.
Impact of aging and comorbidities on ischemic stroke outcomes in preclinical animal models: A translational perspective
2021, Experimental NeurologyCitation Excerpt :The obesity-stroke paradox and contradictory clinical data may be explained by poor design of the human epidemiological studies or the influence of other factors such as age, ethnicity, and sex-specific differences on the interpretation and analysis of the data, as discussed in recent reviews (Haley and Lawrence, 2016; Scherbakov et al., 2011). What is clear from preclinical studies is that obesity results in exacerbated brain injury and more BBB disruption and brain edema, which leads to worse neurobehavioral outcomes in rodent models of focal cerebral ischemia (Deng et al., 2014; Deutsch et al., 2009; Haley et al., 2019; Haley and Lawrence, 2017; Haley et al., 2017; Langdon et al., 2011; Li et al., 2013; Maysami et al., 2015; Osmond et al., 2010; Ritter et al., 2011). Mice fed a high-fat diet for 10 weeks have increased cerebrovascular tortuosity and decreased lumen diameter of the middle cerebral artery.
Blood-brain barrier dysfunction and recovery after ischemic stroke
2018, Progress in NeurobiologyCitation Excerpt :In both patients and animal models, hyperlipidemia is associated with EC dysfunction. Chronic hyperlipidemia induces profound vascular remodeling, such as increased tortuosity index (Deng et al., 2014), increased collagen deposition and vessel stiffness (Deutsch et al., 2009), which worsens the perfusion defects and BBB breakdown after ischemic brain injury (Ayata et al., 2013). In animal models with HFD or ApoE deficiency, hyperlipidemia exacerbates BBB breakdown and brain edema after ischemia, as shown in several reports (Deng et al., 2014; ElAli et al., 2011; Lynch et al., 2002; Methia et al., 2001).
Neuroprotective Potential of Brown Seaweed Phytochemicals in Rodent Models of Cerebral Ischemia
2023, Journal of Medicinal Food