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A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation
Abstract
This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism, and treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups; 20-wk old food-controlled (CON-20); 20-wk old free-food access (model of obesity, OB-20); 40-wk old food-controlled (CON-40); 40-wk old free-food access (OB-40); and 40-wk old free-food access+RUN (RUN-40; wheel-running access from 20-40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere-infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P≤0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P≥0.56) and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P<0.01). At 40-wk of age, cerebellum BF decreased during the EHC in the OB-40 group (P=0.02), but not CON or RUN groups (P≥0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P<0.01). These findings indicate OB-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased NO signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.
... Furthermore, it improves the plasma lipoprotein profile and increases insulin sensitivity and cardiac output (Luan et al., 2019). Exercise improves glycemic control, insulin sensitivity, and fatty acid uptake in adipose tissue, skeletal muscle cells, and endothelium in patients with diabetes mellitus (Olver et al., 2017). In summary, physical activity is widely accepted as an effective therapy in the treatment and prevention of diseases. ...
Blood vessels are key conduits for the transport of blood and circulating factors. Abnormalities in blood vessels promote cardiovascular disease (CVD), which has become the most common disease as human lifespans extend. Aging itself is not pathogenic; however, the decline of physiological and biological function owing to aging has been linked to CVD. Although aging is a complex phenomenon that has not been comprehensively investigated, there is accumulating evidence that cellular senescence aggravates various pathological changes associated with aging. Emerging evidence shows that approaches that suppress or eliminate cellular senescence preserve vascular function in aging-related CVD. However, most pharmacological therapies for treating age-related CVD are inefficient. Therefore, effective approaches to treat CVD are urgently required. The benefits of exercise for the cardiovascular system have been well documented in basic research and clinical studies; however, the mechanisms and optimal frequency of exercise for promoting cardiovascular health remain unknown. Accordingly, in this review, we have discussed the changes in senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) that occur in the progress of CVD and the roles of physical activity in CVD prevention and treatment.
... Rodents with obesity-induced insulin resistance fed a high fat diet showed hypoperfusion of hippocampal vasculature and reduced eNOS which was associated with cognitive deficits (Fu et al., 2017). Evidence suggests that aerobic exercise training may reverse impaired insulin signaling in the cerebrovasculature of rodents with genetically-induced obesity (Olver et al., 2017). ...
... Regular aerobic exercise is widely recognised as a nonpharmacological approach to either reduce or prevent CVD morbidity and mortality. In animal models, aerobic exercise decreases blood TAG, increases HDL cholesterol (Mann et al., 2014), lowers blood pressure (Pedrinolla et al., 2018), improves glucose metabolism and insulin sensitivity (Asuako et al., 2017), reduces body weight and inflammation (Szostak & Laurant, 2011), and improves endothelial function and the bioavailability of nitric oxide (NO) (Medeiros et al., 2016;Olver et al., 2017). Finally, it modulates the expression of proteins and the micro-RNAs (miRs) that are enrolled in cell proliferation, protein synthesis, angiogenesis and anti-apoptotic events (Medeiros et al., 2016;Neves et al., 2014). ...
New findings:
What is the central question of this study? What are the mechanisms underlying the cardiac protective effect of aerobic training in the progression of a high fructose-induced cardiometabolic disease in Wistar rats? What are the main findings and their importance? At the onset of cardiovascular disease, aerobic training activates the p-p70s6k, ERK, and the IRß-PI3K-AKT pathways, without changing the miR-126 and miR-195 levels, therefore, providing evidence that aerobic training modulates the insulin signalling pathway. This data contributes to the understanding of the molecular cardiac changes that are associated with physiological left ventricular hypertrophy during the development of a cardiovascular disease.
Abstract:
Introduction: During the onset of cardiovascular disease (CVD), disturbances in myocardial vascularisation, cell proliferation, and protein expression are observed. Aerobic training prevents CVD but the underlying mechanisms behind left ventricle hypertrophy are not fully elucidated.
Aim:
To investigate the mechanisms by which aerobic training protects the heart from left ventricle (LV) hypertrophy during the onset of a fructose-induced cardiometabolic disease.
Methods:
Male Wistar rats were allocated into four groups (n = 8/group): Control Sedentary (C), Control Training (CT), Fructose Sedentary (F), and Fructose Training (FT). C and CT received drinking water, and the F and FT groups received d-fructose (10% water). After 2 weeks, the CT and FT rats were assigned to a treadmill training protocol at moderate intensity for eight weeks (60 min/day, 4 days/week). After ten weeks, LV morphological remodelling, cardiomyocyte apoptosis, microRNAs, and the insulin signalling pathway were investigated.
Results:
The F group had systemic cardiometabolic alterations, which were normalised by aerobic training. The LV weight increased in FT, myocardium vascularisation decreased in F, and the cardiomyocyte area increased in CT, F, and FT. Regarding the protein expressions, total-IRß decreased in the F. The p-IRß and PI3K increased in the FT. The total-AKT and p-AKT increased in all of the groups. The p-p70s6k protein was higher in the CT, and the p-ERK increased in CT and FT. MiR-126, miR-195, and cardiomyocyte apoptosis did not differ among the groups.
Conclusion:
Aerobic training activates p-p70s6k and p-ERK, and during the onset of a cardiovascular disease, it can activate the IRß-PI3K-AKT pathway. This article is protected by copyright. All rights reserved.
... Six weeks of voluntary wheel running also appears to increase capillarization and VEGF levels in the hippocampus of middle-aged mice (302). Chronic physical activity after the onset of obesity also improved insulinmediated vasodilation in the cerebral vessels in middle-aged rats (303). These aforementioned exercise-induced microvascular protective effects likely can be attributed, at least in part, to reduced systemic inflammatory status. ...
Over two thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.
... Because exercise is known to increase skeletal muscle insulin sensitivity, it is paramount to understand the role exercise dose on affecting insulin-mediated brain glucose metabolism. Recently, wheel running in obese rats with T2D indicated that exercise was capable of improving insulin-stimulated posterior cerebral artery vasodilation in association with nitric oxide and reduced ET-1 signaling (109). Moreover, Ruegsegger et al. reported that exercise improved brain insulin sensitivity of rodents fed a high-fat diet (110). ...
Metformin and exercise independently improve glycemic control. Metformin traditionally is considered to reduce hepatic glucose production, while exercise training is thought to stimulate skeletal muscle glucose disposal. Collectively, combining treatments would lead to the anticipation for additive glucose regulatory effects. Herein, we discuss recent literature suggesting that metformin may inhibit, enhance or have no effect on exercise mediated benefits toward glucose regulation, with particular emphasis on insulin sensitivity. Importantly, we address issues surrounding the impact of metformin on exercise induced glycemic benefit across multiple insulin sensitive tissues (e.g., skeletal muscle, liver, adipose, vasculature, and the brain) in effort to illuminate potential sources of inter-individual glycemic variation. Therefore, the review identifies gaps in knowledge that require attention in order to optimize medical approaches that improve care of people with elevated blood glucose levels and are at risk of cardiovascular disease.
... No changes were observed in the Barnes maze with OLETE rats at 40 weeks of age or in Sprague-Dawley rats on an ultra-processed diet termed the cafeteria diet at 4 months of age, or in learning go/no-go task in OZR (Gomez-Smith et al., 2016;Olver et al., 2017) just as the present study found no difference in set shift task learning, memory, or behavioural flexibility. Interestingly in the operant conditioning tasks OZR had significantly more omissions in the visual cue discrimination task and trended towards increased omissions over the lean controls in the other two tasks. ...
Metabolic syndrome is a highly prevalent constellation of pathologies that frequently combines overweight/obesity, moderate hypertension, atherogenic dyslipidemia, and type II diabetes mellitus, and is accompanied by a systemic vascular pro‐inflammatory, pro‐oxidant condition. The evolution of metabolic syndrome is associated with elevated cerebrovascular disease risk including elevations in both the occurrence and the severity of stroke and transient ischemic attacks within the cerebral circulation. Frequently, these impairments to cerebral vascular function also result in cognitive and behavioral impairments to the afflicted individual even in the absence of an acute pathological event.
Given the established elevation in depressive symptoms in OZR that develop in parallel to cerebrovascular dysfunction, we sought to determine the extent to which cognition was impaired.
In this study 17–18‐wk‐old male lean and (LZR) obese Zucker rats (OZR) were tested for learning, memory, and behavioral flexibility using an operant conditioning chamber (OCC) and the Morris Water Maze (MWM). Learning was assessed by number of trials to reach 8 correct consecutive responses in OCC or a 6 trial MWM protocol. Performance in a retrieval or probe session 24 h after learning was used to measure memory in OCC and MWM respectively. Behavioral flexibility was measured by analyzing error types in OCC and search strategy in the MWM probe test. Depressive symptoms were measured using coat score, novelty suppressed feeding response, and latency to start grooming and frequency of subsequent grooming after sucrose spray. Ex vivo pressurized middle cerebral arteries (MCA) were used to determine the extent to which metabolic syndrome in OZR alters key indices of vascular reactivity of cerebral resistance vessels and the mechanics of the vascular wall.
Endothelium dependent vasodilator reactivity was attenuated in OZR vs LZR in response to acetylcholine. Further impairments were demonstrated in OZR with an increase in depressive symptoms as measured by an increase in coat score and latency to start grooming after sucrose spray as well as mild cognitive impairment measured by increased time to reach the platform in MWM learning trials. In contrast, no signs of cognitive impairment were demonstrated in OCC. These results suggest that the changes in cerebrovascular function in OZR are associated with the development of depressive symptoms and mild cognitive impairment in MWM learning with no changes in learning, memory, or behavior flexibility in OCC at this age.
Support or Funding Information
CIHR (#130138 and #389769); NSERC (RGPIN‐2018‐05450)
... Cohen's d effect sizes were calculated (41)(42)(43) to determine the magnitude and direction of change in protein markers and lipid profiles. Differences between protein markers and lipid profiles were analyzed using a two-way ANOVA (OVX by AB). ...
Post-menopausal women with heart failure (HF) frequently exhibit cardiogenic dementia. Using a pre-clinical swine model of post-menopausal HF, we recently demonstrated that experimental menopause (ovariectomy; OVX) and HF (6-month cardiac pressure overload/aortic banding; AB) independently altered cerebral vasomotor control and together impaired cognitive function. The purpose of this study was to examine the prefrontal cortex and hippocampus tissues from these animals to assess whether OVX and HF are associated with neurologic alterations that may contribute to cardiogenic dementia. We hypothesized that OVX and HF would independently alter neuronal cell signaling in swine with post-menopausal cardiogenic dementia. Immunoblot analyses revealed OVX was associated with reduced estrogen receptor-α in both brain regions and HF tended to exacerbate OVX-induced deficits in the hippocampus. Further, OVX was associated with a reduction in the ratio of phosphorylated:total Akt and ERK in the hippocampus as well as decreased total Akt and synaptophysin in the prefrontal cortex. In contrast, HF was associated with a trend toward reduced phosphorylated:total ERK in the prefrontal cortex. In addition, HF was associated with decreased β-amyloid (1–38) in the prefrontal cortex and increased β-amyloid (1–38) in the hippocampus. Regional brain lipid analysis revealed OVX tended to increase total, saturated, and monounsaturated fatty acid content in the prefrontal cortex, with the greatest magnitude of change occurring in the AB-OVX group. The data from this study suggest that OVX and HF are independently associated with regional-specific neurologic changes in the brain that contribute to the cardiogenic dementia profile in this model. This pre-clinical swine model may be a useful tool for better understanding post-menopausal cardiogenic dementia pathology and developing novel therapies.
... Similarly, exercise prevented diastolic dysfunction likely due to declines in oxidative stress and improved mitochondrial architecture (Bostick et al., 2017). In addition, chronic exercise therapy in obese rats led to restoration of insulin-mediated vasodilation as well as improvements and skeletal muscle and cerebral microcirculation (Olver et al., 2017). Additional studies are needed to fully understand mechanisms responsible for exercise-induced changes at the vascular level in obese populations. ...
Obesity is a global pandemic associated with macro- and microvascular endothelial dysfunction. Microvascular endothelial dysfunction has recently emerged as a significant risk factor for the development of cognitive impairment. In this review, we present evidence from clinical and preclinical studies supporting a role for obesity in cognitive impairment. Next, we discuss how obesity-related hyperinsulinemia/insulin resistance, systemic inflammation, and gut dysbiosis lead to cognitive impairment through induction of endothelial dysfunction and disruption of the blood brain barrier. Finally, we outline the potential clinical utility of dietary interventions, exercise, and bariatric surgery in circumventing the impacts of obesity on cognitive function.
... Indeed, it has been found that even a single low-intensity (50% VO 2 max, 350 kcal expended) exercise session results in significantly improved insulin sensitivity and fatty acid uptake upon examination on the following day (45). Studies in animal models of exercise suggest that increased physical activity can improve insulin sensitivity in adipose tissue, skeletal muscle, and endothelium (46)(47)(48)(49), which are major contributors to systemic insulin resistance in individuals with type 2 diabetes. While our understanding of the precise cellular and molecular mechanisms involved in the enhancement of insulin signaling following exercise has been hampered by inconsistent results across species and exercise protocols, it appears that exercise conditioning is associated with adaptive remodeling in the expression or regulation of one or more components of the insulin receptor/insulin receptor substrate (IRS)/PI3K/Akt signaling cascade (50)(51)(52). ...
It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise.
... Skeletal muscle resistance arteries and 2A pial arteries were dissected using the aid of an Olympus microscope, transferred to a Plexiglas chamber filled with PSS and cannulated with two glass micropipettes (60 -75 m) filled with PSS. The chambers were then transferred to the stage of an inverted microscope (Nikon Diaphot 200) attached to a video camera (Javelin Electronics, Los Angeles, CA), video micrometer (Microcirculation Research Institute, Texas A&M University) and a PowerLab data acquisition system (ADInstruments, Colorado Springs, CO), as previously described (18,19,68,69,79). Fluid-filled reservoirs were used to set intraluminal pressure at 60 cmH2O, and luminal diameter was monitored throughout the experiment. ...
Background:
Impaired microvascular insulin signaling may develop prior to overt indices of microvascular endothelial dysfunction and represent an early pathological feature of adolescent obesity. Using a translational porcine model of juvenile obesity, we tested the hypotheses that in the early stages of obesity development, impaired insulin signaling manifests in skeletal muscle (triceps), brain (prefrontal cortex) and corresponding vasculatures, and that depressed insulin-induced vasodilation is reversible with acute inhibition of protein kinase C beta (PKCβ).
Methods and results:
Juvenile Ossabaw miniature swine (3.5-months of age) were divided into two groups: lean control (n=6) and obese (n=6). Obesity was induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 10-weeks. Juvenile obesity was characterized by excess body mass, hyperglycemia, physical inactivity (accelerometer) and marked lipid accumulation in the skeletal muscle, with no evidence of overt atherosclerotic lesions in athero-prone regions such as the abdominal aorta. Endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) vasomotor responses in the brachial and carotid arteries (wire myography) as well as in the skeletal muscle resistance and 2A pial arterioles (pressure myography) were unaltered, but insulin-induced microvascular vasodilation was impaired in the obese group. Blunted insulin-stimulated vasodilation, which was reversed with acute PKCβ inhibition (LY333-351), occurred alongside decreased tissue perfusion as well as reduced insulin-stimulated Akt signaling in the prefrontal cortex, but not the triceps.
Conclusions:
In the early stages of juvenile obesity development, the microvasculature and prefrontal cortex exhibit impaired insulin signaling. Such adaptations may underscore vascular and neurological derangements associated with juvenile obesity.
... In a study of cerebral vascular function in the animals used in the present study to assess tibial blood flow, NOS-dependent vasodilation was reduced, whereas endothelin-1 (ET-1)-mediated vasoconstriction was increased in isolated cerebral arteries of diabetic O-T2D animals. (59) These observations are consistent with our hypothesis that the T2Dassociated reduction in insulin-stimulated bone blood flow is due to altered insulin vasodilatory response in the vascular endothelium of T2D animals. Although the response of the bone vascular endothelium to insulin appears altered in T2D, the responsiveness of the bone vascular endothelium to other physiologic stimuli, such as exercise or hormones, known to cause vasodilation and increased blood flow in T2D, has not been studied to date. ...
Type 2 diabetes (T2D) increases skeletal fragility and fracture risk; however, the underlying mechanisms remain to be identified. Impaired bone vascular function, in particular insulin-stimulated vasodilation and blood flow is a potential, yet unexplored mechanism. The purpose of this study was to determine the effects of T2D on femoral biomechanical properties, trabecular microarchitecture and insulin-stimulated bone vasodilation by comparison of hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats with normoglycemic control OLETF rats. Four-week old, male OLETF rats were randomized to two groups: type 2 diabetes (O-T2D) or normoglycemic control (O-CON). O-T2D were allowed ad lib access to a rodent chow diet and O-CON underwent moderate caloric restriction (30% restriction relative to intake of O-T2D) to maintain normal body weight (BW) and glycemia until 40 weeks of age. Hyperphagic O-T2D rats had significantly greater BW, body fat, and blood glucose than O-CON. Total cross-sectional area (Tt.Ar), cortical area (Ct.Ar), Ct.Ar/Tt.Ar, and polar moment of inertia of the mid-diaphyseal femur adjusted for BW were greater in O-T2D rats versus O-CON. Whole-bone biomechanical properties of the femur assessed by torsional loading to failure did not differ between O-T2D and O-CON, but tissue-level strength and stiffness adjusted for BW were reduced in O-T2D relative to O-CON. CT of the distal epiphysis showed that O-T2D rats had reduced percent bone volume, trabecular number, and connectivity density and greater trabecular spacing compared with O-CON. Basal tibial blood flow assessed by microsphere infusion was similar in O-T2D and O-CON, but the blood flow response to insulin stimulation in both the proximal epiphysis and diaphyseal marrow was lesser in O-T2D compared to O-CON. In summary, impaired insulin-stimulated bone blood flow is associated with deleterious changes in bone trabecular microarchitecture and cortical biomechanical properties in T2D, suggesting that vascular dysfunction might play a causal role in diabetic bone fragility. This article is protected by copyright. All rights reserved
Introduction: As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which mimic the effects of estrogen. Understanding the impact of soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Methods: Young female C57Bl/6J mice (n=43; ~6 mo) were randomly assigned to 3 groups: Sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX+Soy). Results: In posterior cerebral arteries, OVX mice had a 27% lower maximal response to insulin compared with the Sham mice. The OVX+Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX+Soy and Sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX+Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX+Soy group scored better on nesting behavior compared with both Sham and OVX groups. Conclusion: In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.
Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate limiting enzyme in the production of Aβ. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups (n=12/group): 1) control; 2) exercise training (progressive treadmill training 5 days/week); 3) BDNF (0.5 mg/kg body mass subcutaneous injection 5 days/week); or 4) endurance training and BDNF, for an 8-week intervention. Recognition memory was measured with a novel object recognition test. Serum, the prefrontal cortex, and hippocampus were collected. BDNF improved recognition memory to a similar extent as endurance training. BDNF and exercise decreased BACE1 activity and increased ADAM10 activity in the prefrontal cortex, indicating a shift in APP processing. Our novel results indicate that BDNF exerts similar beneficial effects on cognition and APP processing as exercise. Future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be valuable for populations at risk of AD.
The hypothesis is that the Fidget Factor is the innate neurological pulse that propels humans and other species to move to support their health. Fidgets, previously thought to be spontaneous, are neurologically regulated and highly ordered (non-random). Modern societies being chair-based overwhelm Fidget Factor pulses and consequently inflict chair-based living for transportation, labor, and leisure. Despite impulses firing through the nervous system, people sit because environmental design overwhelms the biology. Urbanization and chair-based societies were designed after the industrial revolution to promote productivity; however, the consequence has been opposite. Crushing the natural urge to move-the Fidget Factor-is a public health calamity. Excess sitting is associated with a myriad of detrimental health consequences and impairs productivity. Fidgeting may reduce all-cause mortality associated with excessive sitting. The Fidget Factor offers hope; data demonstrate that workplaces and schools can be designed to promote activity and free people's Fidget Factors. Evidence shows that people are happier, healthier, wealthier, and more successful if their Fidget Factors are freed.
The etiology of insulin resistance (IR) in Type 1 Diabetes (T1D) is unclear; however, intramyocellular lipids (IMCL) are likely contributors. While exercise lessens IR and IMCL content; T1D patients elevate glycemia to offset exercise-induced hypoglycemic risk. The preferred treatment for T1D patients is tight glucose management through intensive insulin therapy (IIT); however, IIT is accompanied with a sedentary lifestyle. The purpose of this study was to examine IR development and IMCL in combined exercise (DARE; aerobic/resistance) and IIT-treated T1D animals. 76 rats were divided into control sedentary (C), diabetic sedentary (CD), diabetes sedentary intensive insulin therapy (DIT) and DARE groups. Following streptozotocin (STZ), glycemia was maintained at either 9-15 mM (CD, DARE) or 5-9 mM (DIT) using insulin. DARE alternated between running and weighted climbing for 12 weeks. Results demonstrate that DARE exhibited reduced onset of IR compared with C, DIT and CD, indicated by increased glucose infusion rate (hyperinsulinemic-euglycemic-clamp). A shift in lipid metabolism was evident whereby diacylglycerol was elevated in DIT compared to DARE, while triacylglycerol was elevated in DARE. These findings indicate enhanced IMCL metabolism and the sequestration of fat as neutral triacylglycerol leads to reduced IR in DARE. In contrast, IIT and sedentary behavior leads to diacylglycerol accumulation and IR.
Myogenic and flow-induced reactivity contribute to cerebral autoregulation, with potentially divergent roles for smaller vs. larger arteries. The present study tested the hypotheses that compared to first order (1A) branches of the middle cerebral artery, second and third order branches (2A and 3A, respectively) would exhibit greater myogenic reactivity but reduced flow-induced constriction. Further, that nitric oxide synthase (NOS) inhibition would amplify myogenic reactivity and abolish instances of flow-induced dilation. Isolated porcine cerebral arteries mounted in a pressure myograph were exposed to incremental increases in intraluminal pressure (40-120 mmHg; n=40) or flow (1-1170 uL/min; n=31). Intraluminal flow was adjusted to achieve 5, 10, 20 and 40 dynes/cm2 of wall shear stress at 60 mmHg. Myogenic tone was greater in 3A vs. 1A arteries (p<0.05). Linear regression analysis revealed an inverse relationship between myogenic reactivity and passive arterial diameter (p<0.01). Flow-induced dilation was only observed once, and it was blocked with NOS inhibition. Increasing flow decreased luminal diameter (p=0.03), and vasoconstriction was greater at 40, 20 and 10 vs. 5 dynes/cm2 of shear stress (p<0.01). However, relative responses were similar between 1A, 2A and 3A arteries (p=0.40). NOS inhibition increased basal myogenic tone, less so in 3A vs. 1A arteries (p<0.01), but did not influence myogenic reactivity (p=0.49) or flow-induced vasoconstriction (p=0.58). Whereas NOS inhibition increases basal myogenic tone, and myogenic reactivity was less in smaller vs. larger arteries (range= ~100-550 uM), neither NOS inhibition nor luminal diameter influence flow-induced constriction in porcine cerebral arteries.
Inflammation and vascular insulin resistance are hallmarks of type 2 diabetes (T2D). However, the specific mechanisms that cause abnormal endothelial insulin signaling in T2D remain largely unknown. Evidence indicates that the activity of ADAM17 (a disintegrin and metalloproteinase-17) and the presence of insulin receptor (IR) in plasma are increased in T2D subjects. Accordingly, we hypothesized that, in T2D, increased ADAM17 activity sheds the IR ectodomain from endothelial cells and impairs insulin-induced vasodilation. We used small visceral arteries isolated from a cross-sectional study of T2D and non-T2D subjects undergoing bariatric surgery, human cultured endothelial cells, and recombinant proteins to test our hypothesis. Here, we demonstrate that arteries from T2D subjects had increased ADAM17 expression, reduced presence of tissue inhibitor of metalloproteinase-3 (TIMP3), decreased extracellular IRα, and impaired insulin-induced vasodilation vs. those from non-T2D subjects. In vitro, active ADAM17 cleaved the ectodomain of the IRbsubunit. Endothelial cells with ADAM17 overexpression or exposed to the protein kinase-C activator, PMA, hadincreased ADAM17 activity, decreased IRα presence on the cell surface, and increased IR shedding. Moreover, pharmacological inhibition of ADAM17 with TAPI-0 rescued PMA-induced impairments in endothelial insulin signaling and insulin-stimulated vasodilation in human arteries. In aggregate, our findings suggest that ADAM17-mediated shedding of IR from the endothelial surface impairs insulin-mediated vasodilation. Thus, we propose that inhibition of ADAM17 sheddase activity should be considered a strategy to restore vascular insulin sensitivity in T2D.
Sympathetic activity, arteriolar structure and angiogenesis are important mechanisms modulating hypertension and this present study aimed to analyze the effects of perindopril treatment, associated or not with exercise training, on the mechanisms that control blood pressure in hypertensive rats. SHR were allocated into 4 groups: 1/sedentary (S); 2/ perindopril (P, 3.0 mg/kg/day); 3/trained (T) and 4/trained + perindopril (TP). Wistar rats were used as normotensive sedentary control group. SHR were assigned to undergo a treadmill training (T) or were kept sedentary. Heart rate (HR), blood pressure (BP), sympathetic activity to the vessels (LF-SAP), and skeletal muscle and myocardial morphometric analyses were performed. Blood pressure was significantly lower after all 3 strategies, compared with S and was accompanied by lower LF-SAP (-76%, -53% and -44%, for P, T and TP, respectively). Arteriolar vessel wall cross sectional area was lower after treatments (-56%, -52% and -56%, for P, T and TP), and only TP presented higher arteriolar lumen area. Capillary rarefaction was present in soleus muscle and myocardium in S group and both trained groups presented higher vessel density, even though perindopril attenuated this increase in soleus muscle. Although myocyte diameter was not different between groups, myocardial collagen deposition area, higher in S group, was lower after 3 strategies. In conclusion, we may suggest that perindopril could be an option for the hypertensive people who practice exercise and need a specific pharmacological treatment to reach a better BP control, mainly because training-induced angiogenesis is an important response to facilitate blood flow perfusion and oxygen uptake and perindopril did not attenuate this response.
The rapid re‐endothelialization of the vascular stent surface is desirable for preventing thrombosis or reducing restenosis. Many biological factors that promote the biological behavior of endothelial cells have been used for the surface modification of stents. Vascular endothelial growth factor (VEGF), which plays an important role in angiogenesis, induces strong vascular growth. In this study, we investigated different VEGF concentrations (50ng/mL to 500ng/mL) to determine the optimum concentration for biocompatibility. First, VEGF‐loaded heparin/poly‐l‐lysine (Hep‐PLL) nanoparticles were created by electrostatic interactions. Then, the VEGF‐loaded nanoparticles were immobilized on dopamine‐coated 316L stainless steel (SS) surfaces. The physical and chemical properties of the modified surface were characterized and the biocompatibility was evaluated in vitro. The results indicated that the VEGF‐loaded nanoparticles were immobilized successfully on the 316LSS surface, as evidenced by the results of Alcian Blue staining and water contact angle (WCA) measurements. The low platelet adhesion and activation indicated that the modified surfaces had good blood compatibility. The modified surfaces showed a good inhibitory effect on smooth muscle cells, indicating that they inhibited tissue hyperplasia. In addition, the modified surfaces significantly promoted endothelial cell adhesion, proliferation, migration and biological activity, especially VEGF concentration was 350ng/mL(NPV350). The optical VEGF concentration of the surface modified Hep‐PLL nanoparticles was 350ng/mL. The proposed method shows promise for potential applications for cardiovascular devices. This article is protected by copyright. All rights reserved.
Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed PI3K activation and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared to lean subjects. Next, we extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity.
This chapter reviews (1) current knowledge of the mechanisms underlying the pathogenesis of the vascular complications of type 1 and 2 diabetes and (2) current clinical approaches to preventing these.
Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus, experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNFα (~400%) and IL-1β (~1,500%) mRNA (p<0.0001) after 6-weeks. Five days after LPS injections, half of LPS injected rats either performed 3 days/week of RT by ladder climbing for 6-weeks, while half remained without ladders. RT for 6-weeks increased lean body mass percentage (p<0.05), individual muscle masses (gastrocnemius and tibialis anterior) (p<0.05), and maximum lifting capacity (p<0.001). The RT group, compared to sedentary controls, had: 1) ameliorated spatial learning deficits (p<0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, AKT and GSK3β proteins (p<0.05), components of downstream IGF-I signaling, and 3) increased dentate gyrus synaptic-plasticity-marker SYN1 protein (p<0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-week training duration, phosphorylation of ERK1/2 and GSK3β proteins, as well as proliferation-marker protein, PCNA, were significantly increased (p < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus.
We present the hypothesis that exercise-induced hyperemia, perhaps through vascular shear stress, represents an important factor responsible for the effects of physical activity (PA) on vascular insulin sensitivity. Specifically, we postulate PA involving the greatest amount of skeletal muscle mass and the greatest central neural recruitment maximizes perfusion and consequently enhances vascular insulin sensitivity in the skeletal muscle and brain.
Background and Aim
Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging-induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of caloric restriction (CR) preventing the aging-induced insulin resistance in the heart of male Wistar rats.
Methods and results
Three experimental groups were used: 3 months old rats (3m), 24 months old rats (24m) and 24 months old rats subjected to 20% CR during their three last months of life (24m-CR). After sacrifice hearts were mounted in a perfusion system (Langendorff) and heart function in basal conditions and in response to accumulative doses of insulin (10⁻⁹-10⁻⁷ M), in the presence or absence of Wortmannin (10⁻⁶ M), was recorded. CR did not attenuate the aging-induced decrease in coronary artery vasodilation in response to insulin administration, but it prevented the aging-induced downregulation of cardiac contractility (dp/dt) through activation of the PI3K/Akt intracellular pathway. Insulin stimulated in a greater extent the PI3K/Akt pathway vs the activation of the MAPK pathway and increased the protein expression of IR, GLUT-4 and eNOS in the hearts of 3m and 24m-CR rats, but not in the hearts of 24m rats. Furthermore, CR prevented the aging induced increase in endothelin-1 protein expression in myocardial tissue.
Conclusion
In conclusion CR partially improves cardiac insulin sensitivity and prevents the aging induced decrease in myocardial contractility in response to insulin administration through activation of PI3K/Akt pathway.
This review is focused on the factors and potential mechanisms that are causing various cardiovascular pathologies. In diabetes, insulin's actions on the endothelium and other vascular cells have significant influence on systemic metabolisms and the development of cardiovascular pathologies. Our studies showed that insulin receptors on the endothelium are important for insulin transport across the endothelial barrier and mediate insulin's actions in muscle, heart, fat, and the brain. Insulin actions on the vascular cells are mediated by two pathways involving the actions of either IRS/PI3K/Akt or Grb/Shc/MAPK. Insulin's activation of IRS/PI3K/Akt results in mostly antiatherogenic actions, as this pathway induces activation of eNOS, the expressions of HO-1 and VEGF, and the reduction of VCAM-1. In contrast, insulin's activation of the Grb/Shc/MAPK pathway mediates the expressions of ET-1 and PAI-1 and migration and proliferation of contractile cells, which have proatherogenic actions. Elevated levels of glucose, free fatty acids, and inflammatory cytokines due to diabetes and insulin resistance selectively inhibit insulin's antiatherogenic actions via the IRS/PI3K/Akt pathway. This review provides evidence to support the importance of insulin actions in preventing cardiovascular pathology that can be selectively inhibited via the IRS/PI3K/Akt cascade in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress.
Insulin stimulates nerve arterial vasodilation through a nitric-oxide synthase (NOS) mechanism. Experimental diabetes reduces vasa nervorum NO-reactivity. Studies investigating hyperglycemia and nerve arterial vasodilation typically omit insulin-treatment and use sedentary rats resulting in severe hyperglycemia. We tested the hypotheses that i) insulin-treated experimental diabetes and inactivity (DS) will attenuate insulin-mediated nerve arterial vasodilation and ii) deficits in vasodilation in DS rats will be overcome by concurrent exercise training (DX; 75-85% VO2max, 1 h/d, 5 d/week, for 10 weeks). The baseline index of vascular conductance values (iVC = nerve blood flow velocity/mean arterial blood pressure) were similar (P≥0.68), but peak iVC and the area under the curve (AUCi) for the iVC during a euglycemic hyperinsulinemic clamp (EHC; 10 mU/kg/min), were lower in DS rats vs. control sedentary (CS) rats and DX rats (P≤0.01). Motor nerve conduction velocity (MNCV) was lower in DS rats vs. CS rats and DX rats (P≤0.01). Compared with DS rats, DX rats expressed greater nerve endothelial NOS (eNOS) protein content (P=0.04). In a separate analysis, we examined the impact of diabetes in exercise trained rats alone. Compared with exercise trained control rats (CX), DX rats had a lower AUCi during the EHC, lower MNCV values and lower sciatic nerve eNOS protein content (P≤0.03). Therefore, vasa nervorum and motor nerve function are impaired in DS rats. Such deficits in rats with diabetes can be overcome by concurrent exercise training. However, in exercise trained rats (CX and DX groups), poorly controlled blood glucose lowers vasa nervorum and nerve function.
Stress robustness by definition, incorporates both stress resistance stress resistance (organisms endure greater stressor intensity or duration before suffering negative consequences) and stress resilience (organisms recover faster after suffering negative consequences). Factors that influence stress robustness include the nature of the stressor, (i.e., controllability, intensity, chronicity) and features of the organism (i.e., age, genetics, sex, and physical activity status). Here we present a novel hypothesis for how physically active versus sedentary living promotes stress robustness in the face of intense uncontrollable stress. Advances in neurobiology have established microglia microglia as an active player in the regulation of synaptic activity, and recent work has revealed mechanisms for modulating glial function, including cross talk between neurons and glia. This chapter presents supporting evidence that the physical activity status of an organism may modulate stress-evoked neuronal-glial responses by changing the CX3CL1-CX3CR1 axis. Specifically, we propose that sedentary animals respond to an intense acute uncontrollable stressor with excessive serotonin (5-HT) and noradrenergic (NE) activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia microglia in the absence of pathogenic signals and consequent hippocampal-dependent memory deficits and reduced neurogenesis. In contrast, physically active animals respond to the same stressor with constrained 5-HT and NE activity and rapidly recovering CX3CL1-CX3CR1 axis responses resulting in the quieting of microglia, and protection from negative cognitive and neurobiological effects of stress.
Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH(4)) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH(4) supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH(4) by GTP-CH induced by insulin promoted NOS uncoupling.
We examined how cerebral blood flow velocity (CBV) and neurovascular coupling is influenced by exercise. Blood velocities in the posterior and middle cerebral arteries (PCAv and MCAv) during rest and cycling exercise at 60% estimated maximal oxygen consumption were measured. Neurovascular coupling was quantified as the ΔPCAv with visual stimulation. During exercise, despite a 15.2±13.6% and 26.1±22.5% increase from rest in the MCAv and PCAv, respectively, neurovascular coupling was unaltered. Thus, despite regionally heterogeneous elevations in CBV during exercise, neurometabolic coupling is maintained.
To assess the effects of aerobic exercise training on neurocognitive performance. Although the effects of exercise on neurocognition have been the subject of several previous reviews and meta-analyses, they have been hampered by methodological shortcomings and are now outdated as a result of the recent publication of several large-scale, randomized, controlled trials (RCTs).
We conducted a systematic literature review of RCTs examining the association between aerobic exercise training on neurocognitive performance between January 1966 and July 2009. Suitable studies were selected for inclusion according to the following criteria: randomized treatment allocation; mean age > or =18 years of age; duration of treatment >1 month; incorporated aerobic exercise components; supervised exercise training; the presence of a nonaerobic-exercise control group; and sufficient information to derive effect size data.
Twenty-nine studies met inclusion criteria and were included in our analyses, representing data from 2049 participants and 234 effect sizes. Individuals randomly assigned to receive aerobic exercise training demonstrated modest improvements in attention and processing speed (g = 0.158; 95% confidence interval [CI]; 0.055-0.260; p = .003), executive function (g = 0.123; 95% CI, 0.021-0.225; p = .018), and memory (g = 0.128; 95% CI, 0.015-0.241; p = .026).
Aerobic exercise training is associated with modest improvements in attention and processing speed, executive function, and memory, although the effects of exercise on working memory are less consistent. Rigorous RCTs are needed with larger samples, appropriate controls, and longer follow-up periods.
The benefits of fitness for cognitive performance in healthy older adults have repeatedly been demonstrated. Animal studies, however, have revealed differential relationships between physical and motor fitness and brain metabolism. We therefore investigated whether for older humans different dimensions of fitness are differentially associated with cognitive performance and brain activation patterns. Seventy-two participants (mean age 68.99 years, SD = 3.66; 52 females) completed four psychometric tests reflecting two primary abilities of higher cognitive functioning (executive control, perceptual speed) and a battery of fitness tests comprising two fitness dimensions (physical and motor fitness). We found that not only physical fitness indexed by cardiovascular fitness and muscular strength, but also motor fitness including movement speed, balance, motor coordination and flexibility showed a strong association with cognitive functioning. Additionally, functional brain imaging data revealed that physical and motor fitness were differentially related to cognitive processes. Results are discussed with regard to the compensation hypothesis and potential consequences for intervention work.
Effects of insulin on cerebral arteries have never been examined. Therefore, we determined cerebrovascular actions of insulin in rats. Both PCR and immunoblot studies identified insulin receptor expression in cerebral arteries and in cultured cerebral microvascular endothelial cells (CMVECs). Diameter measurements (% change) of isolated rat cerebral arteries showed a biphasic dose response to insulin with an initial vasoconstriction at 0.1 ng/mL (-9.7%+/-1.6%), followed by vasodilation at 1 to 100 ng/mL (31.9%+/-1.4%). Insulin also increased cortical blood flow in vivo (30%+/-8% at 120 ng/mL) when applied topically. Removal of reactive oxygen species (ROS) abolished the vasoconstriction to insulin. Endothelial denudation, inhibition of K(+) channels, and nitric oxide (NO) synthase, all diminished insulin-induced vasodilation. Inhibition of cytochrome P450 enhanced vasodilation in endothelium-intact arteries, but promoted vasoconstriction after endothelial denudation. Inhibition of cyclooxygenase abolished vasoconstriction and enhanced vasodilation to insulin in all arteries. Inhibition of endothelin type A receptors enhanced vasodilation, whereas endothelin type B receptor blockade diminished vasodilation. Insulin treatment in vitro increased Akt phosphorylation in cerebral arteries and CMVECs. Fluorescence studies of CMVECs showed that insulin increased intracellular calcium and enhanced the generation of NO and ROS. Thus, cerebrovascular responses to insulin were mediated by complex mechanisms originating in both the endothelium and smooth muscle.
Neurophysiological and behavioral measures were obtained from 32 senescent (28--34 mo) and 32 mature adult (10--16 mo) rats. Extracellularly recorded synaptic responses were obtained from electrodes chronically implanted in the fascia dentata and perforant path. The rats were first tested on a circular platform, which favored the use of spatial cues for its solution, and the senescent rats were shown to exhibit poorer memory for the rewarded place. When granule cell synaptic responses were recorded after a single session of very brief high-frequency stimulation, the amount of elevation and time course of decline were equivalent between age groups. Af ter three repetitions, however, the young rats maintained the increased synaptic strength for at least 14 days, whereas the old rats declined after the first session. The amount of synaptic enhancement was statistically correlated with the ability to perform the circular platform task both within and between groups. Furthermore, the aftereffects of the high-frequency stimulation selectively impaired the old rats' spontaneous alternation behavior on a T-maze. Certain other neurophysiological and electroencephalographic measures did not distinguish between age groups. The results are discussed in terms of the synaptic theory of memory formation and of their relevance to the aging process.
Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.
Acute occlusion of one common carotid artery in the anesthetized normocapnic rat results in a moderate cerebral blood flow (CBF) decrease in both cerebral hemispheres. No asymmetrical perfusion is observed when the overall flow in each hemisphere is considered. The increase in blood flow which normally occurs in hypercapnia is strongly impaired in the cerebral hemisphere on the occluded side resulting in an important asymmetrical hemispheric perfusion. The days (1, 5, 15, 30) following unilateral carotid occlusion normal control CBF values are found in both hemispheres in normocapnic conditions. Hemispheric perfusion asymmetry in hypercapnia also becomes progressively less pronounced with time but a slight asymmetry still persists one month after unilateral carotid occlusion.
The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.
Evidence accumulated from clinical and basic research has indirectly implicated the insulin receptor (IR) in brain cognitive functions, including learning and memory (Wickelgren, I. (1998) Science 280, 517-519). The present study investigates correlative changes in IR expression, phosphorylation, and associated signaling molecules in the rat hippocampus following water maze training. Although the distribution of IR protein matched that of IR mRNA in most forebrain regions, a dissociation of the IR mRNA and protein expression patterns was found in the cerebellar cortex. After training, IR mRNA in the CA1 and dentate gyrus of the hippocampus was up-regulated, and there was increased accumulation of IR protein in the hippocampal crude synaptic membrane fraction. In the CA1 pyramidal neurons, changes in the distribution pattern of IR in particular cellular compartments, such as the nucleus and dendritic regions, was observed only in trained animals. Although IR showed a low level of in vivo tyrosine phosphorylation, an insulin-stimulated increase of in vitro Tyr phosphorylation of IR was detected in trained animals, suggesting that learning may induce IR functional changes, such as enhanced receptor sensitivity. Furthermore, a training-induced co-immunoprecipitation of IR with Shc-66 was detected, along with changes in in vivo Tyr phosphorylation of Shc and mitogen-activated protein kinase, as well as accumulation of Shc-66, Shc-52, and Grb-2 in hippocampal synaptic membrane fractions following training. These findings suggest that IR may participate in memory processing through activation of its receptor Tyr kinase activity, and they suggest possible engagement of Shc/Grb-2/Ras/mitogen-activated protein kinase cascades.
Despite intensive study, the relation between insulin's action on blood flow and glucose metabolism remains unclear. Insulin-induced changes in microvascular perfusion, independent from effects on total blood flow, could be an important variable contributing to insulin's metabolic action. We hypothesized that modest, physiologic increments in plasma insulin concentration alter microvascular perfusion in human skeletal muscle and that these changes can be assessed using contrast-enhanced ultrasound (CEU), a validated method for quantifying flow by measurement of microvascular blood volume (MBV) and microvascular flow velocity (MFV). In the first protocol, 10 healthy, fasting adults received insulin (0.05 mU. kg(-1). min(-1)) via a brachial artery for 4 h under euglycemic conditions. At baseline and after insulin infusion, MBV and MFV were measured by CEU during continuous intravenous infusion of albumin microbubbles with intermittent harmonic ultrasound imaging of the forearm deep flexor muscles. In the second protocol, 17 healthy, fasting adults received a 4-h infusion of either insulin (0.1 mU. kg(-1). min(-1), n = 9) or saline (n = 8) via a brachial artery. Microvascular volume was assessed in these subjects by an alternate CEU technique using an intra-arterial bolus injection of albumin microbubbles at baseline and after the 4-h infusion. With both protocols, muscle glucose uptake, plasma insulin concentration, and total blood flow to the forearm were measured at each stage. In protocol 2 subjects, tissue extraction of 1-methylxanthine (1-MX) was measured as an index of perfused capillary volume. Caffeine, which produces 1-MX as a metabolite, was administered to these subjects before the study to raise plasma 1-MX levels. In protocol 1 subjects, insulin increased muscle glucose uptake (180%, P < 0.05) and MBV (54%, P < 0.01) and decreased MFV (-42%, P = 0.07) in the absence of significant changes in total forearm blood flow. In protocol 2 subjects, insulin increased glucose uptake (220%, P < 0.01) and microvascular volume (45%, P < 0.05) with an associated moderate increase in total forearm blood flow (P < 0.05). Using forearm 1-MX extraction, we observed a trend, though not significant, toward increasing capillary volume in the insulin-treated subjects. In conclusion, modest physiologic increments in plasma insulin concentration increased microvascular blood volume, indicating altered microvascular perfusion consistent with a mechanism of capillary recruitment. The increases in microvascular (capillary) volume (despite unchanged total blood flow) indicate that the relation between insulin's vascular and metabolic actions cannot be fully understood using measurements of bulk blood flow alone.
Exercise training is considered to be beneficial in the treatment and prevention of insulin insensitivity, and much of the effect occurs in muscle. We have recently shown that capillary recruitment by insulin in vivo is associated with and may facilitate insulin action to increase muscle glucose uptake. In the present study, we examined the effect of 14 days of voluntary exercise training on euglycemic-hyperinsulinemic clamped (10 mU. min(-1). kg(-1) for 2 h), anesthetized rats. Whole-body glucose infusion rate (GIR), hindleg glucose uptake, femoral blood flow (FBF), vascular resistance, and capillary recruitment, as measured by metabolism of infused 1-methylxanthine (1-MX), were assessed. In sedentary animals, insulin caused a significant (P < 0.05) increase in FBF (1.6-fold) and capillary recruitment (1.7-fold) but a significant decrease in vascular resistance. In addition, hindleg glucose uptake was increased (4.3-fold). Exercise training increased insulin-mediated GIR (24%), hindleg glucose uptake (93%), and capillary recruitment (62%) relative to sedentary animals. Neither capillary density nor total xanthine-oxidase activity in skeletal muscle were increased as a result of the training regimen used. We concluded that exercise training improves insulin-mediated increases in capillary recruitment in combination with augmented muscle glucose uptake. Increased insulin-mediated glucose uptake may in part result from the improved hemodynamic control attributable to exercise training.
Many promising findings from pre-clinical research have failed to translate to the clinic due to their inability to incorporate human disease co-morbidity. A variety of rodent diets and feeding durations are currently used in models of human metabolic syndrome, obesity and diabetes. One model, the Cafeteria (CAF) diet, makes use of grocery store-purchased food items that more closely approximate the human ultra-processed diet than commercial high-fat or high-sugar rodent diets. The present study describes the development of metabolic syndrome in rats fed a CAF diet as well as the recovery of metabolic syndrome following a healthy “lifestyle” change. In addition, we explored the effects of CAF diet on spatial learning and memory and on neuroinflammation. Three-week old male Sprague-Dawley rats were fed a CAF diet for three months that consisted of 16 highly palatable human food items along with standard chow and a 12% sucrose solution to mimic soda consumption. Thereafter, a sub-group of CAF diet rats was switched to a chow diet (SWT) for one month. Both CAF and SWT groups were compared to control rats maintained on a standard chow diet (SD). Prior to the diet switch, CAF and SWT animals developed features akin to metabolic syndrome. Both groups of rats displayed significant abdominal obesity with increased visceral adiposity, hyperinsulinemia, glucose intolerance and dyslipidemia with elevated serum triglyceride levels and reduced HDL cholesterol. Switching to a chow diet for one month completely reversed these features in SWT animals. Although acquisition of the Barnes maze was not affected by the CAF diet, these animals exhibited greater hippocampal neuroinflammation compared to both SD and SWT rats as assessed by Iba1 staining. These results demonstrate that the CAF diet is very effective in creating metabolic syndrome with hippocampal inflammation in rats over a relatively short time span. This model may be of great heuristic importance in determining potential reversibility of metabolic and cerebrovascular pathologies across the lifespan and as a co-morbid factor in other disease models such as stroke.
Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance.Wealso describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.
Type 2 diabetes (T2D) alters capillary hemodynamics, causes capillary rarefaction in skeletal muscle and alters endothelial and vascular smooth muscle cell phenotype. These changes contribute to altered blood flow responses to physiological stimuli such as; exercise and insulin secretion. T2D-induced microvascular dysfunction impairs glucose and insulin delivery to skeletal muscle (and other tissues such as skin and nervous), thereby reducing glucose uptake and perpetuating hyperglycemia and hypersinsulinemia. In patients with T2D, exercise training (EX) improves microvascular vasodilator and insulin signaling, and attenuates capillary rarefaction in skeletal muscle. EX-induced changes augment glucose/ insulin delivery and glucose uptake. If these adaptions occur in a sufficient amount of tissue, and skeletal muscle in particular, chronic exposure to hyperglycemia and hyperinsulinemia, and as the risk of microvascular complications in all vascular beds will decrease. We postulate that EX-programs that engage as much skeletal muscle mass, and recruit as many muscle fibers within each muscle, as possible will generate the greatest improvements in microvascular function, providing the duration of the stimulus is sufficient. Primary improvements in microvascular function occur in tissues (skeletal muscle primarily) engaged during exercise and secondary improvements in microvascular function throughout the body may result from improved blood glucose control. We propose that the added benefit of combined resistance and aerobic EX programs and of vigorous intensity EX programs is not simply "more is better". Rather, the additional benefit is the result of EX-induced adaptations in and around more muscle fibers, resulting in more muscle mass, and the associated microvasculature, being changed.
What is the topic of this review? This review highlights the importance of increased vascular insulin sensitivity for maintaining glycaemic control and cardiovascular health. What advances does it highlight? We discuss the role of habitual physical activity in modulating vascular actions of insulin. Type 2 diabetes and cardiovascular disease commonly coexist. Current evidence suggests that impaired insulin signalling in the vasculature may be a common link between metabolic and cardiovascular diseases, including glycaemic dysregulation and atherosclerosis. Herein, we highlight the importance of the actions of insulin on the vasculature for glycaemic control and arterial health. In addition, we summarize and discuss findings from our group and others demonstrating that increased physical activity may be an effective approach to enhancing vascular insulin sensitivity. Furthermore, in light of the existing literature, we formulate the hypothesis that increased shear stress may be a prime mechanism through which habitual physical activity improves insulin signalling in the vasculature. Ultimately, we propose that targeting vascular insulin resistance may represent a viable strategy for improving glycaemic control and reducing cardiovascular risk in patients with type 2 diabetes.
© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.
We examine evidence supporting the associations among physical activity (PA), cognitive vitality, and neural functioning, and the moderation of these associations by genetic factors. Prospective epidemiological studies provide evidence for PA to be associated with a modest reduction in relative risk of cognitive decline. An evaluation of the PA-cognition link across the life span provides modest support for the effect of PA on preserving and even enhancing cognitive vitality and the associated neural circuitry in older adults; the majority of benefits seen are for tasks that are supported by the prefrontal cortex and the hippocampus. The literature on children and young adults, however, is in need of well-powered randomized controlled trials. Future directions include a more sophisticated understanding of the dose-response relationship, the integration of genetic and epigenetic approaches, inclusion of multimodal imaging of brain-behavior changes, and finally the design of multimodal interventions that may yield broader improvements in cognitive function. Expected final online publication date for the Annual Review of Psychology Volume 66 is November 30, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Background
Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance. Objective
Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle. Methods
Insulin signaling and vasoreactivity to insulin (1–1000 μIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks. ResultsGlucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p < 0.05 vs. SED12), and maintained in CR20. Insulin-stimulated vasodilation was greater in Gw but not Gr, 2As of RUN20 (p < 0.01 vs. all groups), and was improved by ET-1 receptor inhibition in Gw 2As from SED20 and CR20 (p < 0.05). There were no differences in microvascular insulin signaling among groups or muscle beds. ConclusionsRUN selectively improved insulin-mediated vasodilation in Gw 2As, in part through attenuated ET-1 sensitivity/production, an adaptation that was independent of changes in adiposity and may contribute to enhanced insulin-stimulated glucose disposal.
New findings
What is the central question of this study?
This study investigated the influence of obesity on insulin‐induced vasomotor reactivity in rat skeletal muscle feed arteries.
What is the main finding and its importance?
Irrespective of obesity, the gastrocnemius feed artery displayed diminished insulin‐induced vasodilatory response compared to the soleus feed artery. This difference between the arteries was abolished in the presence of an endothelin‐1 receptor antagonist. Therefore, our findings demonstrate that insulin‐induced endothelin‐1 production is not uniform among all skeletal muscle resistance vessels.
The vascular actions of insulin are complex, because it can stimulate both nitric oxide‐mediated dilatation and endothelin (ET)‐1‐mediated constriction. We examined vasoreactivity to insulin in isolated feed arteries of the gastrocnemius (GFA) and soleus muscles (SFA) of 32‐week‐old Long–Evans Tokushima Otsuka (LETO) and Otsuka Long–Evans Tokushima fatty (OLETF) rats, a hyperphagic rodent model of obesity and insulin resistance. The insulin‐induced vasoreactivity of SFA and GFA was similar in LETO (healthy) and OLETF (obese/insulin‐resistant) rats. However, examination of between‐vessel effects revealed a number of novel insights into the heterogeneous vascular effects of insulin. Soleus feed arteries dilated more than GFA in LETO at 100 and 1000 μIU ml ⁻¹ insulin (23 versus 6 and 28 versus 0%, respectively; P < 0.05 for between‐vessel differences). Likewise, in OLETF rats there was significantly greater dilatation in SFA than GFA at 10, 100 and 1000 μIU ml ⁻¹ insulin (28 versus 3, 30 versus 0 and 34 versus 0%, respectively; all P < 0.05). In the presence of 3 μ m tezosentan, a non‐specific endothelin‐1 receptor blocker, insulin‐induced dilatation of the GFA was enhanced such that differences between vessels were largely abolished in both groups. Furthermore, acetylecholine‐induced dilatation was significantly greater in SFA than GFA within each group, whereas sodium nitroprusside‐induced dilatory responses were greater in the GFA compared with the SFA. Overall, our findings indicate that the insulin/endothelin‐1 vasoconstrictor pathway is more active in GFA than in SFA, independent of obesity in the OLETF rat model.
To test the hypothesis that chronic metformin treatment enhances insulin-induced vasodilation in skeletal muscle resistance arteries and arterioles.
We assessed the effect of metformin treatment (from 20-32 wks of age) of obese Otsuka Long Evans Tokushima Fatty (OLETF) rats and lean Long Evans Tokushima Otsuka (LETO) rats (300 mg/kg) on insulin-stimulated vasodilation in isolated skeletal muscle feed arteries and arterioles.
Metformin treatment significantly lowered food intake, body weight, percent body fat, and glycosylated hemoglobin (HbA1c) in OLETF rats. Metformin resulted in a ~30% reduction in insulin-induced vasodilation of soleus feed arteries (SFA) from OLETF rats. Inhibition of endothelin-1 (ET-1) signaling produced 20% dilation and eliminated the difference between metformin-treated and untreated OLETF rats in insulin-induced dilation of SFA. In contrast to the SFA, metformin did not alter insulin-stimulated vasodilation in gastrocnemius feed arteries (GFA), or 2(nd) order arterioles in the red (G2A-R) or white (G2A-W) portions of the gastrocnemius muscle of OLETF rats. Metformin had no effects on vasomotor responses of arteries from LETO.
Although metformin exerts favorable effects on body composition and HbA1c, it does not enhance the vasodilatory responses to insulin in the skeletal muscle feed arteries or arterioles of the obese OLETF rat. This article is protected by copyright. All rights reserved.
Cardiovascular actions of insulin were studied by intravenous infusions of insulin (4 and 8 mU/kg per min) in normal conscious dogs. This resulted in increases in cardiac output, heart rate, and left ventricular derivative of pressure with respect to time (dP/dt) and dP/dt/P, as blood glucose was reduced. The inotropic and chronotropic effects of insulin were not related to hypoglycemia, as they persisted even when blood glucose was restored to control values or when it was prevented from falling by a simultaneous infusion of glucose. These cardiac effects were accompanied by increases in plasma catecholamines, and were abolished by propranolol pretreatment. Both plasma epinephrine and norepinephrine increased during insulin hypoglycemia, but only norepinephrine increased during insulin infusion when euglycemia was maintained.
Mean arterial blood pressure did not change significantly during insulin hypoglycemia, but rose if euglycemia was maintained, probably due to the selective increase in norepinephrine in the latter condition. A pressor response also occurred in propranolol-pretreated dogs during insulin hypoglycemia, but was abolished when the animals also had been pretreated with phentolamine, indicating that the vasoconstrictor action of insulin was mediated via alpha adrenergic receptors.
Insulin infusion increased left ventricular work and myocardial blood flow in dogs with and without hypoglycemia. Myocardial blood flow, however, did not change significantly during insulin infusion in dogs pretreated with propranolol. As propranolol also diminished the inotropic response, it appears that the increase in myocardial blood flow caused by insulin in the normal dog is causally related to the increased myocardial metabolic demand.
Insulin also produced vasomotor effects on other vascular beds. In skeletal muscle, blood flow was increased under all study conditions, except during insulin hypoglycemia after propranolol-pretreatment when unopposed alpha-mediated vasoconstriction was present. The persistent increase in flow during both alpha and beta adrenergic blockade suggests that insulin has a direct dilator effect on skeletal muscle vasculature. In the adrenal gland, flow was increased except during euglycemia, when no rise in plasma epinephrine was observed, suggesting coupling between adrenal flow and catecholamine release. In the splanchnic bed, flow was decreased during euglycemia, when plasma norepinephrine rose, and during beta adrenergic blockade with propranolol, when unopposed alpha-mediated vasoconstriction also predominated. A similar pattern was found in the kidney, except that renal blood flow also fell after combined alpha and beta adrenergic blockade. The results show that the vasomotor effects on regional flows are mediated both via adrenergic mechanisms, and in the case of skeletal muscle and kidney, via mechanisms unrelated to sympathetic stimulation.
• The purpose of these experiments was to use radiolabelled microspheres to measure blood flow distribution within the brain, and in particular to areas associated with motor function, maintenance of equilibrium, cardiorespiratory control, vision, hearing and smell, at rest and during exercise in miniature swine. Exercise consisted of steady-state treadmill running at intensities eliciting 70 and 100 % maximal oxygen consumption (V˙O2,max). • Mean arterial pressure was elevated by 17 and 26 % above that at rest during exercise at 70 and 100 %V˙O2,max, respectively. • Mean brain blood flow increased 24 and 25 % at 70 and 100 %V˙O2,max, respectively. Blood flow was not locally elevated to cortical regions associated with motor and somatosensory functions during exercise, but was increased to several subcortical areas that are involved in the control of locomotion. • Exercise elevated perfusion and diminished vascular resistance in several regions of the brain related to the maintenance of equilibrium (vestibular nuclear area, cerebellar ventral vermis and floccular lobe), cardiorespiratory control (medulla and pons), and vision (dorsal occipital cortex, superior colliculi and lateral geniculate body). Conversely, blood flow to regions related to hearing (cochlear nuclei, inferior colliculi and temporal cortex) and smell (olfactory bulbs and rhinencephalon) were unaltered by exercise and associated with increases in vascular resistance. • The data indicate that blood flow increases as a function of exercise intensity to several areas of the brain associated with integrating sensory input and motor output (anterior and dorsal cerebellar vermis) and the maintenance of equilibrium (vestibular nuclei). Additionally, there was an intensity-dependent decrease of vascular resistance in the dorsal cerebellar vermis.
GREENWOOD, B. N. and M. FLESHNER. Exercise, stress resistance, and central serotonergic systems. Exerc. Sport Sci. Rev., Vol. 39, No. 3, pp. 140-149, 2011. Voluntary exercise reduces the incidence of stress-related psychiatric disorders in humans and prevents serotonin-dependent behavioral consequences of stress in rodents. Evidence reviewed herein is consistent with the hypothesis that exercise increases stress resistance by producing neuroplasticity at multiple sites of the central serotonergic system, which all help to limit the behavioral impact of acute increases in serotonin during stressor exposure.
The mechanism underlying the plateau or relative decrease in cerebral blood flow (CBF) during maximal incremental dynamic exercise remains unclear. We hypothesized that cerebral perfusion is limited during high-intensity dynamic exercise due to a redistribution of carotid artery blood flow. To identify the distribution of blood flow among the arteries supplying the head and brain, we evaluated common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA) and vertebral artery (VA) blood flow during dynamic exercise using Doppler ultrasound. Ten subjects performed graded cycling exercise in a semi-supine position at 40, 60 and 80% of peak oxygen uptake (VO2 peak) for 5 min at each workload. The ICA blood flow increased by 23.0 ± 4.6% (mean ± SE) from rest to exercise at 60% (VO2 peak). However, at 80% (VO2 peak), ICA blood flow returned towards near resting levels (9.6 ± 4.7% vs. rest). In contrast, ECA, CCA and VA blood flow increased proportionally with workload. The change in ICA blood flow during graded exercise was correlated with end-tidal partial pressure of CO2 (r = 0.72). The change in ICA blood flow from 60% (VO2 peak) to 80% (VO2 peak) was negatively correlated with the change in ECA blood flow (r = −0.77). Moreover, there was a significant correlation between forehead cutaneous vascular conductance and ECA blood flow during exercise (r = 0.79). These results suggest that during high-intensity dynamic exercise the plateau or decrease in ICA blood flow is partly due to a large increase in ECA blood flow, which is selectively increased to prioritize thermoregulation.
This study provides an examination of spatial learning and a behavioral assessment of irritability and locomotion in TgCRND8 mice, an amyloid precursor protein transgenic model of Alzheimer's disease. Performance was assessed using the Barnes maze, the touch escape test, and an open-field test. While past research focused primarily on 2-5-month-old TgCRND8 mice, the present study used an older age cohort (9-month-old female mice), in addition to a 4-month-old cohort of both transgenic (Tg) and wildtype female mice. Both younger and older Tg mice displayed poor spatial learning in the Barnes maze task compared to their wildtype littermates, as demonstrated by significantly longer latencies and more errors both during acquisition and at a 2-week retest. No differences in irritability were found between Tg and control mice in the younger cohort; however, older Tg mice displayed significantly higher irritability compared with wildtype littermates, as measured by the touch escape test. Additionally, Tg mice of both age cohorts showed increased locomotion and slowed habituation during a 60-min open-field test over 3 days of testing. These results demonstrate that TgCRND8 mice show significant deficits in spatial and nonspatial behavioral tasks at advanced stages of amyloid pathology.
Insulin-mediated glucose disposal is dependent on the vasodilator effects of insulin. In type 2 diabetes, insulin-stimulated vasodilation is impaired as a result of an imbalance in NO and ET-1 production. We tested the hypothesis that chronic voluntary wheel running (RUN) prevents impairments in insulin-stimulated vasodilation associated with obesity and type 2 diabetes independent of the effects of RUN on adiposity by randomizing Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of hyperphagia-induced obesity and type 2 diabetes, to 1) RUN, 2) caloric restriction (CR; diet adjusted to match body weights of RUN group), or 3) sedentary control (SED) groups (n = 8/group) at 4 wk. At 40 wk, NO- and ET-1-mediated vasoreactivity to insulin (1-1,000 μIU/ml) was assessed in the presence of a nonselective ET-1 receptor blocker (tezosentan) or a NO synthase (NOS) inhibitor [N(G)-nitro-L-arginine methyl ester (L-NAME)], respectively, in second-order arterioles isolated from the white portion of the gastrocnemius muscle. Body weight, fasting plasma glucose, and hemoglobin A1c were lower in RUN and CR than SED (P < 0.05); however, the glucose area under the curve (AUC) following the intraperitoneal glucose tolerance test was lower only in the RUN group (P < 0.05). Vasodilator responses to all doses of insulin were greater in RUN than SED or CR in the presence of a tezosentan (P < 0.05), but group differences in vasoreactivity to insulin with coadministration of L-NAME were not observed. We conclude daily wheel running prevents obesity and type 2 diabetes-associated declines in insulin-stimulated vasodilation in skeletal muscle arterioles through mechanisms that appear to be NO mediated and independent of attenuating excess adiposity in hyperphagic rats.
In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model.
OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group).
At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.
Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.
The pathogenesis of type 2 diabetes is intimately intertwined with the vasculature. Insulin must efficiently enter the bloodstream from pancreatic beta-cells, circulate throughout the body, and efficiently exit the bloodstream to reach target tissues and mediate its effects. Defects in the vasculature of pancreatic islets can lead to diabetic phenotypes. Similarly, insulin resistance is accompanied by defects in the vasculature of skeletal muscle, which ultimately reduce the ability of insulin and nutrients to reach myocytes. An underappreciated participant in these processes is the vascular pericyte. Pericytes, the smooth muscle-like cells lining the outsides of blood vessels throughout the body, have not been directly implicated in insulin secretion or peripheral insulin delivery. Here, we review the role of the vasculature in insulin secretion, islet function, and peripheral insulin delivery, and highlight a potential role for the vascular pericyte in these processes.
Little is known of the course and distribution of blood vessels supplying and draining the hippocampus. Such information could be of value in designing and evaluating lesion and ablation experiments and may reflect spatial properties of neurons. This study mapped the distribution of major arteries and veins of the rat hippocampal formation. Arteries and veins of adult female Wistar rats anesthetized with sodium pentobarbital were injected with silicone rubber. Double injections to demonstrate both arteries and veins in the same animal were with India ink and a fluorescent material. Arterial supply to the hippocampus was via transverse hippocampal arteries that stemmed from the longitudinal hippocampal artery, a branch of the posterior cerebral artery. Internal transverse hippocampal arteries located in the hippocampal fissure supplied small, short branches to the adjacent blade of the fascia dentata, part of the area dentata, and CA3 fields. Other branches of the longitudinal artery supplied the remaining blade of the fascia and area dentata, subicular fields, and entorhinal structures. Internal transverse hippocampal veins located in the hippocampal fissure alternated in position with the arteries and appeared to be paired with, and to drain fields supplied by, the internal transverse arteries. Deep transverse hippocampal veins, unaccompanied by arteries, received branches in the intraventricular alveus and adjacent stratum oriens of CA3. The transverse veins drained into longitudinal vessels or the basal vein. Although transversely directed arteries and veins may suggest a hippocampal lamellar neuronal organization, microvascular fields must be mapped before claims are made for a totally segmental vascular architecture in the hippocampus.
The influence of marked arterial hypoxia combined with unilateral carotid artery clamping upon regional cortical metabolites and blood flow was studied in the rat brain. When the arterial Po, was reduced to about 20 mm Hg the hemisphere on the clamped side showed a marked lactic acidosis and a fall in phosphocreatine but the adenylate energy charge remained close to normal. In this hemisphere, the cortical blood flow increased about 4-fold. On the clamped side there was an excessive lactic acidosis and a marked fall in energy charge. However, since the levels of glucose, glucose-6-phosphate and pyruvate did not fall below normal, and since the regional blood flow was at least doubled, it is concluded that the derangement of the energy metabolism was due to cellular hypoxia, exaggerated by the relative ischemia induced by the carotid artery clamping. The biochemical lesion was most pronounced in the distribution territory of the middle cerebral artery that also showed the largest degree of relative ischemia. It is suggested that the pronounced lactic acidosis may contribute to the neuronal damage observed with this model of hypoxia and relative ischemia.
Male mice which were allowed wheel exercise during a late stage in the life-span had a small, but statistically reliable increment
in longevity, compared with control male mice. Differences in longevity were not statistically reliable for experimental and
control female mice. However, longevity was significantly positively correlated with wheel exercise for both male and female
experimental mice. The behavioral effects of access to activity wheels were to increase scores of exploration activity and
decrease scores of emotionality compared with scores of controls. Albino hybrid mice lived as long as pigmented (brown or
black) hybrid mice. The albino gene, as expressed in F2hybrids, was not found to be deleterious for measures of longevity, or behavioral measures of wheel activity, exploration,
and emotionality.
Cardiovascular actions of insulin were studied by intravenous infusions of insulin (4 and 8 mU/kg per min) in normal conscious dogs. This resulted in increases in cardiac output, heart rate, and left ventricular derivative of pressure with respect to time (dP/dt) and dP/dt/P, as blood glucose was reduced. The inotropic and chronotropic effects of insulin were not related to hypoglycemia, as they persisted even when blood glucose was restored to control values or when it was prevented from falling by a simultaneous infusion of glucose. These cardiac effects were accompanied by increases in plasma catecholamines, and were abolished by propranolol pretreatment. Both plasma epinephrine and norepinephrine increased during insulin hypoglycemia, but only norepinephrine increased during insulin infusion when euglycemia was maintained. Mean arterial blood pressure did not change significantly during insulin hypoglycemia, but rose if euglycemia was maintained, probably due to the selective increase in norepinephrine in the latter condition. A pressor response also occurred in propranolol-pretreated dogs during insulin hypoglycemia, but was abolished when the animals also had been pretreated with phentolamine, indicating that the vasoconstrictor action of insulin was mediated via alpha adrenergic receptors. Insulin infusion increased left ventricular work and myocardial blood flow in dogs with and without hypoglycemia. Myocardial blood flow, however, did not change significantly during insulin infusion in dogs pretreated with propranolol. As propranolol also diminished the inotropic response, it appears that the increase in myocardial blood flow caused by insulin in the normal dog is causally related to the increased myocardial metabolic demand. Insulin also produced vasomotor effects on other vascular beds. In skeletal muscle, blood flow was increased under all study conditions, except during insulin hypoglycemia after propranolol-pretreatment when unopposed alpha-mediated vasoconstriction was present. The persistent increase in flow during both alpha and beta adrenergic blockade suggests that insulin has a direct dilator effect on skeletal muscle vasculature. In the adrenal gland, flow was increased except during euglycemia, when no rise in plasma epinephrine was observed, suggesting coupling between adrenal flow and catecholamine release. In the splanchnic bed, flow was decreased during euglycemia, when plasma norepinephrine rose, and during beta adrenergic blockade with propranolol, when unopposed alpha-mediated vasoconstriction also predominated. A similar pattern was found in the kidney, except that renal blood flow also fell after combined alpha and beta adrenergic blockade. The results show that the vasomotor effects on regional flows are mediated both via adrenergic mechanisms, and in the case of skeletal muscle and kidney, via mechanisms unrelated to sympathetic stimulation.
A method for multiple simultaneous determinations of cardiocirculatory dynamics, regional blood flow, and total cardiac output distribution in the conscious rat preparation is described. The preparation allows for intravenous administration of agents and can be performed on animals either at rest or during treadmill exercise. Instrumentation procedures involve placement of fluid-filled catheters in the left ventricle, right atria, right jugular vein, and caudal artery. Left ventricular pressures are recorded via a modified 4F Millar transducer-tipped manometer containing a 10-cm extension of fluid-filled PE 50 placed into the left ventricle via the right carotid artery. Radionuclide-labeled microspheres (15 +/- 5 mu) are injected into the left ventricle through the fluid-filled PE 50 at selected times for determination of cardiac output and regional blood flows using the caudal artery catheter as the source of the reference blood sample. Details and selected validation data for procedures involving anesthesia, instrumentation, recovery from anesthesia, data gathering, and data analysis are presented. Emphasis is placed on the procedures required for use of the radioactive microsphere technique in this model with special attention given to quality control of the microsphere stock, counting procedures, and computer analysis of these data.
The common carotid artery is often ligated and used to introduce a left ventricular catheter to perform blood flow studies with radioactive-labeled microspheres. In order to determine whether this procedure alters brain blood flow, 6 newborn piglets were studied. Five measures of brain blood flow were performed in each study; once before and then 4 times (at 20 min intervals) after ligation of the left common carotid artery. Ventilation was controlled using nitrous oxide and oxygen while the hematocrit was kept stable by intermittent transfusions. Brain blood flow was found to remain constant over the duration of the study. No differences in blood flow were found between the right and left sides of the brain. The data indicate that use of a common carotid artery for purposes of left ventricular catheterization do not alter the blood flow to the brain when the microsphere method is used. This facilitates surgical preparation when small animals are used for studies of brain blood flow hemodynamics.
Physical training increases insulin action in skeletal muscle in healthy men. In non-insulin-dependent diabetes mellitus (NIDDM), only minor improvements in whole-body insulin action are seen. We studied the effect of training on insulin-mediated glucose clearance rates (GCRs) in the whole body and in leg muscle in seven patients with NIDDM and in eight healthy control subjects. One-legged training was performed for 10 weeks. GCR in whole body and in both legs were measured before, the day after, and 6 days after training by hyperinsulinemic (28, 88, and 480 mU x min(-1) x m(-2)), isoglycemic clamps combined with the leg balance technique. On the 5th day of detraining, one bout of exercise was performed with the nontraining leg. Muscle biopsies were obtained before and after training. Whole-body GCRs were always lower (P < 0.05) in NIDDM patients compared with control subjects and increased (P < 0.05) in response to training. In untrained muscle, GCR was lower (P < 0.05) in NIDDM patients (13 +/- 4, 91 +/- 9, and 148 +/- 12 ml/min) compared with control subjects (56 +/- 12, 126 +/- 14, and 180 +/- 14 ml/min). It Increased (P < 0.05) in both groups in response to training (43 +/- 10, 144 +/- 17, and 205 +/- 24 [NIDDM patients] and 84 +/- 10, 212 +/- 20, and 249 +/- 16 ml/min [control subjects]). Acute exercise did not increase leg GCR. In NIDDM patients, the effect of training was lost after 6 days, while the effect lasted longer in control subjects. Training increased (P < 0.05) muscle lactate production and glucose storage as well as glycogen synthase (GS) mRNA in both groups. We conclude that training increases insulin action in skeletal muscle in control subjects and NIDDM patients, and in NIDDM patients normal values may be obtained. The increase in trained muscle cannot fully account for the increase in whole-body GCR. Improvements in GCR involve enhancement of insulin-mediated increase in muscle blood flow and the ability to extract glucose. They are accompanied by enhanced nonoxidative glucose disposal and increases in GS mRNA. The improvements in insulin action are short-lived.
The purpose of this study was to evaluate the effect of angiotensin-converting enzyme (ACE) inhibition on collateral-dependent blood flow (BF) during exercise. Adult male Sprague-Dawley rats (approximately 320 g) were fed zabicipril, an ACE inhibitor, mixed with powdered food at 0.0, 0.3, and 3.0 mg.kg-1 x day-1 (n = 12/group) for 5-7 days. Under ketamine-acepromazine anesthesia, the carotid and caudal arteries were catheterized for BF determination, and both femoral arteries were ligated to remove the primary route for BF to the distal limb tissue. Later on the same day, collateral-dependent hindlimb BF was determined at two treadmill speeds (15 and 25 m/min at 15% grade) with 85Sr- and 141Ce-labeled 15-microns microspheres. Zabicipril ingestion induced 50 and 65% inhibition of plasma ACE activity in the low- and high-dose group, respectively (P < 0.001). ACE inhibition did not affect body weight, blood pressure, or heart rate of the rats during exercise. However, BFs to the total hindlimb were 44 and 36% higher (P < 0.001) in zabicipril-treated animals than in the zero-dose controls (approximately 45 ml.min-1 x 100 g-1). Furthermore, BFs to the proximal hindlimb, distal hindlimb, and gastrocnemius-plantaris-soleus group were 33-44% greater in drug-treated than in control animals (P < 0.025). Higher speed (25 m/min) failed to further increase muscle BF; therefore peak BFs were likely achieved. These results indicate that collateral-dependent BF was improved by ACE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
We investigated whether blood flow determined by a flow probe situated on one common carotid artery provided an accurate estimation of unilateral cerebral blood flow (CBF) in piglets. In eight anesthetized, mechanically ventilated piglets, blood flow determined by an ultrasonic flow probe placed on the right common carotid artery was correlated with CBF determined by microspheres under two experimental conditions: 1) before ligation of the right external carotid artery with both the right external and internal carotid circulations intact [common carotid artery blood flow (CCABF) condition], and 2) after ligation of the right external carotid artery (ipsilateral to the flow probe) with all residual right-sided carotid artery blood flow directed through the right internal carotid artery [internal carotid artery blood flow (ICABF) condition]. The left carotid artery was not manipulated in any way in either protocol. Independent correlations of unilateral CCABF and ICABF with microsphere-determined unilateral CBF were highly significant over a 5-fold range of CBF induced by hypercarbia or hypoxia (r = 0.94 and 0.92, respectively; both p < 0.001). The slope of the correlation of unilateral CCABF versus unilateral CBF was 1.68 +/- 0.19 (SEM), suggesting that CCABF overestimated CBF by 68%. The slope of the correlation of unilateral ICABF versus unilateral CBF did not differ significantly from unity (1.06 +/- 0.15), and the y intercept did not differ significantly from zero [-1.3 +/- 5.2 (SEM) mL]. Consequently, unilateral ICABF determined by flow probe accurately reflected unilateral CBF determined by microspheres under these conditions. Flow probe assessments of CCABF and ICABF in piglets may provide information about dynamic aspects of vascular control in the cerebral circulation that has heretofore been unavailable.
Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. As OLETF rats lack CCK-A receptor because of a genetic abnormality, we examined whether learning and memory were impaired in these animals using an elevated eight-arm radial maze. After the completion of a radial maze study, the animals were sacrificed for histological examination of the brain. In some animals, long-term potentiation (LTP) in the hippocampus was measured. In the radial maze, the level of activity (seconds/entry) and the time remaining in the arms were significantly longer in OLETF rats. The number of errors was also significantly higher, and that of the correct choices was significantly lower in OLETF rats compared to the controls (LETO rats). The LTP of the population spike was significantly lower in the OLETF than in the LETO rats. No histological abnormalities were observed. From these observations, we concluded that learning and memory functions were impaired in the OLETF rats.
The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties.
Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (P=0. 88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (P<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N(G)-monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (P=0.006).
These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.
Insulin receptors are known to be located on nerve cells in mammalian brain. The binding of insulin to dimerized receptors stimulates specialized transporter proteins that mediate the facilitated influx of glucose. However, neurons possess other mechanisms by which they obtain glucose, including transporters that are not insulin-dependent. Further, insulin receptors are unevenly distributed throughout the brain (with particularly high density in choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex). Such factors imply that insulin, and insulin receptors, might have functions within the central nervous system in addition to those related to the supply of glucose. Indeed, invertebrate insulin-related peptides are synthesized in brain and serve as neurotransmitters or neuromodulators. The present review summarizes the structure, distribution and function of mammalian brain insulin receptors and the possible implications for central nervous system disorders. It is proposed that this is an under-studied subject of investigation.
Cholecystokinin (CCK) may have a role in the mediation of human panic disorder and anxiogenic (anxiolytic)-like activity in an animal model of anxiety. Otsuka Long Evans Tokushima Fatty (OLETF) rats lacked CCK A receptors (CCKAR) because of a genetic abnormality. In order to elucidate the involvement of CCKAR in the regulation of anxiety, we investigated the exploratory behavior on elevated plus-maze test, the black and white box test, and open field test with OLETF rats in comparison with normal [Long-Evans Tokushima Otsuka (LETO)] rats. And OLETF rats increased the number of stretched attend postures and decreased open arm entry and the % time of open arm in an elevated plus-maze test. Time spent in the white box decreased significantly in OLETF rats than LETO rats. The total line crossing decreased significantly in OLETF rats compared to LETO rats. The missing CCKAR had a significant anxiogenic-like effect. These data support the involvement of the CCKAR in the neurobiological mechanism of anxiety.
Cholecystokinin (CCK) is deeply involved in the control of learning and emotional behaviors. The authors characterize the behavioral properties of Otsuka Long Evans Tokushima Fatty (OLETF) rats, which lack the CCK-A receptor because of a genetic abnormality. In the Morris water-maze task, the OLETF rats showed an impaired spatial memory. In the inhibitory avoidance test, they showed facilitating response 24 h after training. Hypoalgesia was observed in a hot-plate test. In the elevated plus-maze and food neophobia test, OLETF rats showed an anxiety-like response. In addition, OLETF rats were hypoactive in the Morris water-maze and the elevated plus-maze. The results suggest that the OLETF rats showed a spatial memory deficit, hypoactivity and anxiety due, at least in part, to the lack of CCK-A receptors.