Early effects of high-fat diet on neurovascular function and focal ischemic brain injury

Abstract

-Obesity is a risk factor for stroke, but the early effects of high-fat diet (HFD) on neurovascular function and ischemic stroke outcomes remain unclear. The goal of this study was to test the hypotheses that HFD beginning early in life 1) impairs neurovascular coupling, 2) causes cerebrovascular dysfunction, and 3) worsens short-term outcomes after cerebral ischemia. Functional hyperemia and parenchymal arteriole (PA) reactivity were measured in rats after 8 wk of HFD. The effect of HFD on basilar artery function after middle cerebral artery occlusion (MCAO) and associated O-GlcNAcylation were assessed. Neuronal cell death, infarct size, hemorrhagic transformation (HT) frequency/severity, and neurological deficit were evaluated after global ischemia and transient MCAO. HFD caused a 10% increase in body weight and doubled adiposity without a change in lipid profile, blood glucose, and blood pressure. Functional hyperemia and PA relaxation were decreased with HFD. Basilar arteries from stroked HFD rats were more sensitive to contractile factors, and acetylcholine-mediated relaxation was impaired. Vascular O-GlcNAcylated protein content was increased with HFD. This group also showed greater mortality rate, infarct volume, HT occurrence rate, and HT severity and poor functional outcome compared with the control diet group. These results indicate that HFD negatively affects neurovascular coupling and cerebrovascular function even in the absence of dyslipidemia. These early cerebrovascular changes may be the cause of greater cerebral injury and poor outcomes of stroke in these animals. cerebral ischemia; high-fat diet; hemorrhagic transformation; neurovascular coupling; vascular dysfunction OBESITY IS an independent risk factor for acute ischemic stroke (AIS) (19,36). An alarming recent report showed that the prevalence of AIS dramatically increased in children and young adults, which positively correlated with increases in risk factors including obesity, lipid disorders, and diabetes (13). Clinical studies also suggest that obesity is an independent predictor of unfavorable functional outcome and mortality in AIS patients treated with tissue plasminogen activator (tPA), the only therapeutic option these patients have (39,40). Given that stroke is the leading cause of disability and that the obesity epidemic is on the rise these clinical and social problems are expected to get worse, and therefore early interventions are necessary. While experimental studies in genetic or diet-induced obesity models have shown increased cerebral infarct size and poor outcomes of stroke (7,25,32,33,41), the early impact of a high-fat diet (HFD) before the development of obesity on AIS injury and functional outcomes is not known.It is known that the brain relies heavily on constant blood flow for proper function. Two important mechanisms that contribute to the regulation of cerebral blood perfusion are autoregulatory behavior of cerebral vessels and functional hyperemia upon increased neuronal activity (11,16,20). HFD can negatively af...

Differential Effects of Pioglitazone in the Hippocampal CA1 Region Following Transient Forebrain Ischemia in Low- and High-Fat Diet-Fed Gerbils

“…This result suggests that juvenile exposure to HFD for 8 weeks does not cause any significant differences in neuronal death compared to LFD 4 days after ischemia/reperfusion. This result was supported by previous studies that also showed no difference in hippocampal neuronal death between control diet-and HFD-fed groups after 8 weeks in a rat model of global ischemia [19,20]. In addition, our colleagues do not detect any significant differences in neuronal damage between control diet-and HFD-fed groups after 4 weeks in the gerbil model of transient forebrain ischemia [21].…”

“…In addition, obesity beginning in childhood decreases cerebral vascular function and exacerbates the damage caused by focal ischemia [3,6,7,17,18]. However, obesity does not cause any significant effects on neuronal cell death or survival after global cerebral ischemia [19][20][21].…”

Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

“…Despite recent advances in redox biology and aging research (9,21,27,33,37,49,51,52,55,59,65,72,97), the role of ROS in the cerebromicrovascular effects of CR remains elusive. To assess cellular peroxide production, we used the cell-permeant oxidative fluorescent indicator dye CM-H 2DCFDA [5 (and 6)-chloromethyl-2=,7=-dichlorodihydrofluorescein diacetateacetyl ester; Invitrogen, Carlsbad, CA] as we previously reported (16,86).…”

Cerebrovascular Changes

“…For example, increased cerebral infarct size and poor outcomes of stroke have been observed in a number of genetic and DIO models subsequently induced with ischemia. These studies included models of DIO via administration of a high fat diet (36% fat; high in saturated fat) for 10 weeks (Deutsch et al, 2009), administration of a 'Western Diet' for 12 weeks (Langdon et al, 2011), administration of a high fat diet (45% fat) for 8 weeks (Li et al, 2013), TallyHo mice (a model of type II diabetes) (Didion et al, 2007), the ob/ob mouse (Mayanagi et al, 2008;Kumari et al, 2010), the diabetic db/db mouse (Vannucci et al, 2001), and the obese Zucker rat (Osmond et al, 2009;. In the 2009 study by Deutsch et al, the authors found that the middle cerebral arteries (MCAs) from obese rats had smaller lumens and thicker walls.…”