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Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice
Abstract
Although the increasing rate of obesity has stimulated interest in the effects of diet composition on peripheral systems, comparatively little work has been done to examine effects upon the brain. A diet high in fat is one of many factors that can promote obesity, and previous research has shown that such a diet can produce learning and memory impairment in rodents. In the present study, C57BL/6 mice were placed on either a high-fat (45% kcal fat) or regular (5% kcal fat) diet, and examined at different points during the subsequent year. The high-fat diet led to increased weight gain, significant impairment in glucoregulation, and altered insulin-mediated signaling within the hippocampus, an area of the brain believed to be important for the acquisition of memory. Following ten months on either diet, synaptic function in ex vivo hippocampal slices was examined, and neither stimulus-response curves nor electrically induced long-term potentiation were found to be different. As well, performance in the Morris water maze, a hippocampal-dependent test of spatial memory, was not influenced by diet. However, mice consuming a high-fat diet failed to perform an operant bar-pressing task, indicating a significant impairment to procedural learning and consolidation processes. Despite causing broad peripheral changes in C57BL/6 mice, consuming a large proportion of calories from saturated fat had only a limited effect upon learning and memory, which suggests that certain aspects of brain function are selectively vulnerable to the influences of diet.
... Turning to the experimental evidence on the impact of HFD treatment during late adolescence and young adulthood (i.e., in 6-9-week-old mice and 9-10-week-old rats [91]), (see Table 1), the summarized data show that an adolescent HFD treatment increased anxiety-related and anhedonia-like responses, without reliably affecting stress-coping style [114][115][116][117][118]. It also reduced locomotion, exploration but not social behaviours [116,117,119,120]. In contrast to HFD treatment in juveniles, HFD treatment in adolescents had no major impact on hippocampus-dependent learning and memory [116,121,122]. Similar results of increased emotionality and reduced reward responsiveness have been reported in rodents exposed to physical and/or psychosocial stressors during adolescence [123,124]. ...
... In the hippocampus, a critical brain area for learning and memory, HFD treatment had a minor influence on glucose metabolism and insulin signalling, and no significant impact on glucose transport, amino acid and phospholipid metabolism [105,119,122,127]. As observed for the cerebral cortex, an HFD in adolescence might be associated with a minor molecular insulin resistance, as shown by the lack of activation response of Akt [119]. ...
... For example, HFD treatment significantly affected serotonergic transmission [117,118]. HFD treatment reduced the expression of BDNF, as well as that of key synaptic proteins involved in vesicle trafficking and receptor anchoring; it also reduced the number of dendritic spines and produced some changes in the cytoarchitecture of the hippocampus [117,121,122,127]. Similarly, maternal HFD treatment decreased the length of dendritic spines (without affecting the spine density) and altered astrocyte morphology [89,145]. ...
Affective and substance-use disorders are associated with overweight and obesity-related complications, which are often due to the overconsumption of palatable food. Both high-fat diets (HFDs) and psychostimulant drugs modulate the neuro-circuitry regulating emotional processing and metabolic functions. However, it is not known how they interact at the behavioural level, and whether they lead to overlapping changes in neurobiological endpoints. In this literature review, we describe the impact of HFDs on emotionality, cognition, and reward-related behaviour in rodents. We also outline the effects of HFD on brain metabolism and plasticity involving mitochondria. Moreover, the possible overlap of the neurobiological mechanisms produced by HFDs and psychostimulants is discussed. Our in-depth analysis of published results revealed that HFDs have a clear impact on behaviour and underlying brain processes, which are largely dependent on the developmental period. However, apart from the studies investigating maternal exposure to HFDs, most of the published results involve only male rodents. Future research should also examine the biological impact of HFDs in female rodenrts. Further knowledge about the molecular mechanisms linking stress and obesity is a crucial requirement of translational research and using rodent models can significantly advance the important search for risk-related biomarkers and the development of clinical intervention strategies.
... The results of the study showed that animals that were fed high levels of saturated fats made more working memory errors, such as reentering the same arm twice, than control animals fed a low--fat diet (Granholm et al., 2008). Mielke et al. (2006) conducted a longitudinal study on mice that were fed a forty--five percent fat diet for a year. The researchers used two behavioral tests, the traditional Morris water maze and an operant bar--pressing task, to test memory. ...
... When pressed, this lever would release food pellets on the other side of the cage. In order to reach the reward, the mice had to find an alternate route around an obstacle in the middle of the test cage (Mielke et al., 2006). Mielke et al. (2006) found that high fat fed mice were impaired in the operant--Honors College Research Journal ...
... In order to reach the reward, the mice had to find an alternate route around an obstacle in the middle of the test cage (Mielke et al., 2006). Mielke et al. (2006) found that high fat fed mice were impaired in the operant--Honors College Research Journal ...
... Laboratory rodents are frequently used in research aimed at dissecting the neural and physiological mechanisms that control feeding behavior and body weight (Speakman et al., 2007). Many published studies have demonstrated that obesity compromises memory (Greenwood and Winocur, 1990;Farr et al., 2008;Mielke et al., 2006;Murray et al., 2009;McNeilly et al., 2001;Valladolid-Acebes et al., 2011). Usually, however, the tests use food as the reinforcing stimulus and interpretation of the results do not consider that obese animals have abundant energy supplies and may therefore be less motivated to perform (Peters et al., 2004;Peters and Langemann, 2009;Shin et al., 2011;Kubera et al., 2012). ...
... However, a recent meta-analysis concluded that, whereas executive function may be compromised by obesity in children and adolescents, obesity does not have clear effects on other cognitive domains, such as learning and memory (Liang et al., 2014). Notably, increased body weight and sweet or fatty (high-calorie) diets have been shown to have a negative impact on the performance of laboratory animals in some (Farr et al., 2008;Stranahan et al., 2008;Jurdak and Kanarek, 2009;Ross et al., 2009;Heyward et al., 2012;Valladolid-Acebes et al., 2013;Beilharz et al., 2014) but not all (Mielke et al., 2006;Ross et al., 2009;Hwang et al., 2010;Heyward et al., 2012;Valladolid-Acebes et al., 2013;Beilharz et al., 2014) tests of hippocampus-dependent spatial, recognition and fear learning and memory. Our experiments show that overweight and obese mice perform poorly in pavlovian conditioning and operant conditioning, two paradigms that test appetitive learning paradigms. ...
... It is important to note here that, laboratory animals may differ from humans in that they are less exposed to environments where hedonic signals abound and can override actual metabolic demands. The present findings raise important questions regarding the interpretation of results from overweight and obese rodents in which learning and memory is assessed using paradigms in which food is used as the reinforcing stimulus (e.g., Greenwood and Winocur, 1990;McNeilly et al., 2001;Mielke et al., 2006;Farr et al., 2008;Murray et al., 2009;Valladolid-Acebes et al., 2011). The apparent impaired ability of overweight and obese animals in such tests may simply reflect their reduced motivation (reduced "wanting") to retrieve and consume appetitive rewards, illustrated by our results from a motivation task that did not depend on learning ability (Figure 3). ...
Eating depends strongly on learning processes which, in turn, depend on motivation. Conditioned learning, where individuals associate environmental cues with receipt of a reward, forms an important part of hedonic mechanisms; the latter contribute to the development of human overweight and obesity by driving excessive eating in what may become a vicious cycle. Although mice are commonly used to explore the regulation of human appetite, it is not known whether their conditioned learning of food rewards varies as a function of body mass. To address this, groups of adult male mice of differing body weights were tested two appetitive conditioning paradigms (pavlovian and operant) as well as in food retrieval and hedonic preference tests in an attempt to dissect the respective roles of learning/motivation and energy state in the regulation of feeding behavior. We found that (i) the rate of pavlovian conditioning to an appetitive reward develops as an inverse function of body weight; (ii) higher body weight associates with increased latency to collect food reward; and (iii) mice with lower body weights are more motivated to work for a food reward, as compared to animals with higher body weights. Interestingly, as compared to controls, overweight and obese mice consumed smaller amounts of palatable foods (isocaloric milk or sucrose, in either the presence or absence of their respective maintenance diets: standard, low fat-high carbohydrate or high fat-high carbohydrate). Notably, however, all groups adjusted their consumption of the different food types, such that their body weight-corrected daily intake of calories remained constant. Thus, overeating in mice does not reflect a reward deficiency syndrome and, in contrast to humans, mice regulate their caloric intake according to metabolic status rather than to the hedonic properties of a particular food. Together, these observations demonstrate that excess weight masks the capacity for appetitive learning in the mouse.
... These findings differ from those of other authors. For instance, Mielke's group reported that HFD did not affect synaptic efficacy or LTP (Mielke et al., 2006), whereas other authors have demonstrated impairment of LTP after HFD treatment (Hao et al., 2016). The different periods of HFD treatment and the different protocols for synaptic plasticity processes may be responsible for these discrepancies. ...
... determine, as most studies do not go beyond the identification of insulin resistance indexes (HOMA-IR), which are not indicative of the responsiveness of insulin receptors within brain areas involved in learning/memory. In this regard, the study by Vinuesa et al. (2016) reported that memory impairment triggered by HFD in juvenile mice is associated to specific insulin resistance within the hippocampus, even in the absence of obesity, as already observed by Mielke et al. (2006). These findings are in line with previous studies, carried out in engineered rats, showing that lentiviral deletion of insulin receptors within the hippocampus has a negative influence on hippocampus-dependent learning/memory tasks (Grillo et al., 2011(Grillo et al., , 2015. ...
The negative impact of obesity on neurocognitive functioning is an issue of increasing clinical interest. Over the last decade, a number of studies have analyzed the influence of high-fat diets (HFDs) on cognitive performance, particularly in adolescent individuals. Different approaches, including behavioral, neurochemical, electrophysiological and morphological studies, have been developed to address the effect of HFDs on neural processes interfering with learning and memory skills in rodents. Many of the studies have focused on learning and memory related to the hippocampus and the mechanisms underlying these processes. The goal of the current review article is to highlight the relationship between hippocampal learning/memory deficits and nutritional/endocrine inputs derived from HFDs consumption, with a special emphasis on research showing the effect of HFDs intake during the juvenile period. We have also reviewed recent research regarding the effect of HFDs on hippocampal neurotransmission. An overview of research suggesting the involvement of fatty acid (FA) receptor-mediated signaling pathways in memory deficits triggered by HFDs is also provided. Finally, the role of leptin and HFD-evoked hyperleptinemia is discussed.
... No changes in learning and memory processes were found in HS rats. These results reinforces the view that early life is a period of great vulnerability of the neural substrate that mediates hippocampal-dependent learning and memory processes to certain types of high-caloric diets (Boitard et al., 2014(Boitard et al., , 2012(Boitard et al., , 2015Hsu et al., 2015;Reichelt, 2016;Reichelt, Killcross, Hambly, Morris, & Westbrook, 2015a), as opposed to what happens during adulthood (Boitard et al., 2014;McNeilly et al., 2011;Mielke et al., 2006). In effect, the adult hippocampus seems to be vulnerable to high-caloric diets only under certain conditions, such as after chronic consumption (Farr et al., 2008;Heyward et al., 2012) or feeding with very high caloric diets (Murray et al., 2009;Pistell et al., 2010). ...
... As referred above, the present results corroborate previous studies demonstrating that adolescence is a vulnerable period to diet alterations (Boitard et al., 2014;McNeilly et al., 2011;Mielke et al., 2006;Reichelt, 2016). Indeed, adolescence is a critical period of neurodevelopment with the formation of complex brain networks related to future behavioral regulation and cognition (Boitard et al., 2016). ...
Early life, covering childhood and adolescence in humans, is an important period of brain development and maturation. Experimental works in rodents have shown that high-caloric diets are particularly detrimental to young rats, affecting cognition. We studied the effects of two different high-caloric diets, prevalent in human adolescents, on male Wistar rats aged 4 weeks at the beginning of the experiment. Rats were randomly allocated to control (C, n=10), high-sugar diet (HS, n=10) and cafeteria diet (CAF, n=10) groups and fed accordingly for 8 weeks. At the end of this period, behavioral tests were performed to analyze (1) anxiety behavior in the elevated plus-maze and open field tests, (2) learning and memory processes in the Morris water maze and novel object recognition test, (3) fear response in the fear conditioning test, and (4) depression state in the forced swim test. We also examined neurogenesis in the dentate gyrus using the marker of neuroproliferation doublecortin (DCX). Our results show that CAF rats have impaired spatial learning and memory and increased anxiety, without changes in the remaining aspects of behavior, associated with a reduction of the total number of DCX-immunoreactive cells in the subgranular layer of the dentate gyrus. Conversely, HS rats displayed no changes in behavior and neurogenesis. These data demonstrate that diets rich in saturated fats and sugar are more detrimental for juvenile rats than diets with high sugar content in what concerns their effects in anxiety-related behaviors, spatial learning and memory, and neurogenesis. These findings may help explain the cognitive disturbances observed in obese human adolescents, who consume high-caloric diets.
... In addition, a Western-type diet may impact on reciprocal cognition [5,7] and social interactions [3]. Human and animal studies suggest important roles of increased fat-/cholesterol-containing dietary regimen in behavioural abnormalities associated with social behaviour, aggression, and brain plasticity [7][8][9][10][11][12]. ...
... Together with marketable inflammation that was previously demonstrated in an applied model here [30] and that can be a causal factor of insulin resistance [61], this finding led to suggesting altered insulin-mediated signalling in the brain, where insulin resistance in the hippocampus may account for reported behavioural abnormalities here. The use of high-fat/highcholesterol diets showed that behavioural changes of rodents housed on these diets are accompanied by type II diabetes mellitus [8,10,21,53]. Importantly, heightened occurrence of diabetes and reduced glucose tolerance during autistic spectrum disorder is well established in the literature [62,63]. ...
Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder.
... White adipose tissue size-frequency distribution profiles mirrored these body weight changes, collectively reinforcing the link between obesity, white adipose tissue hypertrophy, and metabolic abnormalities (Lumeng andSaltiel, 2011, Gregor andHotamisligil, 2011). Unlike the other strains examined, B6-wt mice developed early obesity, dyslipidemia, and impaired glucose tolerance as anticipated (Sims et al., 2013, Li et al., 2010, Mielke et al., 2006, Muller et al., 2013, identifying this murine model as the one that most closely replicates human disease. The apparent improvements in insulin sensitivity at 36 wk (in all HFD-fed strains) were somewhat unexpected; however, prolonged HFD-feeding has been reported to result in improved impaired glucose tolerance (Muller et al., 2013). ...
... The apparent improvements in insulin sensitivity at 36 wk (in all HFD-fed strains) were somewhat unexpected; however, prolonged HFD-feeding has been reported to result in improved impaired glucose tolerance (Muller et al., 2013). Moreover, plasma insulin levels remained high in our animals, suggesting that our use of a lower dose of glucose for glucose tolerance testing may have compounded any potential HFD duration-related effects (1 g/kg body weight as per Diabetic Complications Consortium protocol, compared with 2 g/kg body weight in other studies (Sims et al., 2013, Mielke et al., 2006). ...
Patients with the metabolic syndrome, defined as obesity, dyslipidemia, hypertension, and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and the metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of the metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Lepr(db/+), B6-wt, B6-Lepr(db/+), BTBR-wt, and BTBR-Lep(ob/+)) fed a 54% high-fat diet (HFD; from lard). All HFD-fed mice developed large fiber neuropathy and IGT. Changes appeared early and consistently in B6-wt mice, and paralleled the onset of neuropathy. Terminally, B6-wt mice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia, and oxidized low density lipoproteins (oxLDL). Dietary reversal, whereby B6-wt mice fed HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL-cholesterol and oxLDL by 50% compared to HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of the metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy.
... However, deficits in non-spatial memory have also been observed, such as an impairment in reversal learning following classic conditioning for rats fed a high fat diet supplemented with high concentrations of either glucose or sucrose for 3 months (Kanoski et al., 2007), in non-spatial reference and working memory after 30 days of exposure (Kanoski and Davidson, 2010), in fear conditioning (Xu and Südhof, 2013;Spencer et al., 2017), and in novel object recognition (Gainey et al., 2016) or location (Heyward et al., 2012). Together, these findings confirm the hypothesis that high-energy diets alter aspects of hippocampal and cortical function-as well as other brain regions such as the amygdala-to affect learning and memory; a handful of studies, however, failed to show any changes in some types of learning and memory tasks with these diets (Mielke et al., 2006;McNeilly et al., 2011;Heyward et al., 2012). A recently published meta-analysis indicates that in humans diets with high levels of saturated fats, and particularly, those with both saturated fat and added sugars, negatively impacted measures of hippocampal function, such as learning and memory or hippocampal volume (Taylor et al., 2021). ...
In humans, alterations in cognitive, motivated, and affective behaviors have been described with consumption of processed diets high in refined sugars and saturated fats and with high body mass index, but the causes, mechanisms, and consequences of these changes remain poorly understood. Animal models have provided an opportunity to answer these questions and illuminate the ways in which diet composition, especially high-levels of added sugar and saturated fats, contribute to brain physiology, plasticity, and behavior. Here we review findings from invertebrate (flies) and vertebrate models (rodents, zebrafish) that implicate these diets with changes in multiple behaviors, including eating, learning and memory, and motivation, and discuss limitations, open questions, and future opportunities.
... HFD treated Tg2576 mouse had no effect on the level of amyloid beta 1−42 in the cortex and shown more anxious, but had better learning which related to the improvements of BBB function (Elhaik Goldman et al., 2018). HFD had only a limited effect upon learning and memory in C57BL/6 mice despite broad peripheral changes (Mielke et al., 2006;Kesby et al., 2015). These data therefore suggest that different modes of memory are differentially sensitive to the effects of a high-fat diet. ...
Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by the complex interaction of multiple mechanisms. Recent studies examining the effect of high-fat diet (HFD) on the AD phenotype have demonstrated a significant influence on both inflammation and cognition. However, different studies on the effect of high-fat diet on AD pathology have reported conflicting conclusions. To explore the involvement of HFD in AD, we investigated phenotypic and metabolic changes in an AD mouse model in response to HFD. The results indicated there was no significant effect on Aβ levels or contextual memory due to HFD treatment. Of note, HFD did moderate neuroinflammation, despite spurring inflammation and increasing cholesterol levels in the periphery. In addition, diet affected gut microbiota symbiosis, altering the production of bacterial metabolites. HFD created a favorable microenvironment for bile acid alteration and arachidonic acid metabolism in APP/PS1 mice, which may be related to the observed improvement in LXR/PPAR expression. Our previous research demonstrated that Huanglian Jiedu decoction (HLJDD) significantly ameliorated impaired learning and memory. Furthermore, HLJDD may globally suppress inflammation and lipid accumulation to relieve cognitive impairment after HFD intervention. It was difficult to define the effect of HFD on AD progression because the results were influenced by confounding factors and biases. Although there was still obvious damage in AD mice treated with HFD, there was no deterioration and there was even a slight remission of neuroinflammation. Moreover, HLJDD represents a potential AD drug based on its anti-inflammatory and lipid-lowering effects.
... Our behavioral results showed that HSD consumption impairs longterm performance of spatial memory using two different tasks: OLM and WM, which goes in accordance with previous reports (Mielke et al., 2006;Ross et al., 2009). Evident memory impairment was observed on the test trial 24 h later in the group of animals exposed to HSD; these animals spent more time finding the platform and show a reduced number of crossings on the platform area. ...
Increasing evidence suggests that long-term consumption of high-caloric diets increases the risk of developing cognitive dysfunctions. In the present study, we assessed the catecholaminergic activity in the hippocampus as a modulatory mechanism that is altered in rats exposed to six months of a high-sucrose diet (HSD). Male Wistar rats fed with this diet developed a metabolic disorder and showed impaired spatial memory in both water maze and object location memory (OLM) tasks. Intrahippocampal free-movement microdialysis showed a diminished dopaminergic and noradrenergic response to object exploration during OLM acquisition compared to rats fed with normal diet. In addition, electrophysiological results revealed an impaired long-term potentiation (LTP) of the perforant to dentate gyrus pathway in rats exposed to a HSD. Local administration of nomifensine, a catecholaminergic reuptake inhibitor, prior to OLM acquisition or LTP induction, improved long-term memory and electrophysiological responses, respectively. These results suggest that chronic exposure to HSD induces a hippocampal deterioration which impacts on cognitive and neural plasticity events negatively; these impairments can be ameliorated by increasing or restituting the affected catecholaminergic activity.
... Oxidative stress contributes to many neurodegenerative diseases and brain damage, and induces cell injury with impaired learning and memory. Additionally, one study relates Alzheimer's disease to consumption of HFD [31] while other studies attribute this cognitive impairment to other factors such as impaired glucoregulation [32], increased brain inflammation and alteration in blood brain barrier permeability [33]. It has been known that consumption of HFD is associated with significant weight gain and chronic low levels of inflammation together with brain insulin resistance with loss of synaptic plasticity [34]. ...
Intermittent fasting (IF) plays an important role in the protection against metabolic syndrome-induced memory defects. This study aimed to assess the protective effects of both prophylactic and curative IF against high-fat diet (HFD)-induced memory defects in rats. The control group received a normal diet; the second group received a HFD; the third group was fed a HFD for 12 weeks and subjected to IF during the last four weeks (curative IF); the fourth group was fed a HFD and subjected to IF simultaneously (prophylactic IF). A high-fat diet significantly increased body weight, serum lipids levels, malondialdehyde (MDA) concentration, glial fibrillary acidic protein (GFAP) and H score in brain tissue and altered memory performance. In addition, it significantly decreased reduced glutathione (GSH) concentration in brain tissue and viability and thickness of pyramidal and hippocampus granular cell layers. However, both types of IF significantly decreased body weight, serum lipids, GFAP protein expression and H score and MDA concentration in brain tissue, and improved memory performance, while it significantly increased GSH concentration in brain tissue, viability, and thickness of pyramidal and granular cell layers of the hippocampus. This study indicated that IF ameliorated HFD-induced memory disturbance and brain tissue damage and the prophylactic IF was more potent than curative IF.
... Пространственная память была значительно увеличена в группе CR и существенно уменьшилась в группе с высококалорийным питанием (HC), демонстрируя, что длительное потребление высоких калорий вызывает аутофагию в гиппокампе, что может увеличить риск когнитивных нарушений [58]. В тоже время, Mielke J. G. et al. (2006) обнаружили отсутствие влияния HFD на пространственную память [59]. ...
The new competencies of psychoneuroimmunoendocrinology and psychoneuroimmunology play a strategic role in interdisciplinary science and interdisciplinary planning and decision-making. The introduction of multi-vector neurotechnologies of artificial intelligence and the principles of digital health care will contribute to the development of modern neuroscience and neuromarketing. The availability of innovative technologies, such as next-generation sequencing and correlated bioinformatics tools, allows deeper investigation of the cross-network relationships between the microbiota and human immune responses. Immune homeostasis is the balance between immunological tolerance and inflammatory immune responses — a key feature in the outcome of health or disease. A healthy microbiota is the qualitative and quantitative ratio of diverse microbes of individual organs and systems, maintaining the biochemical, metabolic and immune equilibrium of the macroorganism necessary to preserve human health. Functional foods, healthy biomicrobiota, healthy lifestyle and controlled protective environmental effects, artificial intelligence and electromagnetic information load/overload are responsible for the work of the human immune system and its ability to respond to pandemic attacks in a timely manner. Obesity continues to be one of the main problems of modern health care due to its high prevalence and polymorbidity. In addition to cardiometabolic diseases, lesions of the musculoskeletal system, obese individuals show impaired cognitive functions, have a high risk of developing depression and anxiety. The gut microbiota mediates between environmental influences (food, lifestyle) and the physiology of the host, and its change may partially explain the cross-link between the above pathologies. It is known that Western eating patterns are the main cause of the obesity epidemic, which also contributes to dysbiotic drift of the gut microbiota, which in turn contributes to the development of complications associated with obesity. Experimental studies in animal models and, to a lesser extent in humans, show that microbiota is associated with obesity and may contribute to the endocrine, neurochemical and development of systemic inflammation underlying obesity itself and related diseases. Nevertheless, a number of questions remain at present. Modeling the microbiota-gut-brain axis, provides the brain with information from the gut not only through the nervous system but also through a continuous stream of microbial, endocrine, metabolic and immune messages. The communication network provides important keys to understanding how obesity and diabetes can affect the brain by provoking neuropsychiatric diseases. The literature review is devoted to the analysis of data on the relationship of the gut-brain axis, obesity and cognitive functions, immune homeostasis and new competencies: psychoneuroimmunology and psychoneuroimmunoendocrinology.
... In this study, we assessed the cognitive performance of HFD offspring that showed cognitive impairment as assessed by the MWM. Some studies have reported that offspring born to dams fed with an HFD before or during pregnancy [59,60], until the lactation period or adolescence [61] showed cognitive impairments [62][63][64]. However, no previous studies have explored the possible association between the Ob-R expression and the cognitive performance of the offspring exposed to an HFD just during gestation. ...
ABSTRACT
A high-fat diet (HFD) during pregnancy influences the neurodevelopment of progeny, particularly in the hippocampus, a brain region involved in cognitive processes. The hippocampus has high levels of leptin receptors (Ob-R) that participate in synaptic plasticity. This study examined the effect of maternal HFD during gestation on Ob-R expression in the CA1 and CA3 hippocampal regions, and its relationship with spatial learning and memory in the offspring. We used 48 rat pups: 24 from dams fed a balanced diet (BD, 6.2% fat) and 24 from those fed an HFD (42% fat) during pregnancy. We recorded weight gain and food intake in each pup every day beginning on postnatal day 3 (PND 3). Memory acquisition was assessed on PND 28 and memory retention on PND 42 in the Morris water maze (MWM). Then, 12 pups per group were selected randomly and subjected to bioimpedance spectroscopy. The remaining offspring was perfused to determine Ob-R expression levels in the CA1 and CA3 hippocampal regions. Interestingly, HFD pups had significantly higher weight gain, food intake, and fat mass than BD offspring. Interestingly, the HFD group showed poor memory performance, which correlated with changes in the Ob-R expression in both hippocampal regions. These data indicate that maternal exposure to HFD impacts neurodevelopmental and cognitive functions of the offspring.
... Under conditions of excess energy intake, the metabolic handling of substrates is parallel to modifications in the hormonal mechanisms that regulate energy metabolism [235], since the main system of regulation of glycaemia (insulin) has been severely damaged [236]. The other mechanisms complementary to insulin have a wider array of functions: the glucocorticoids, favor liver glucose output under conditions of stress or metabolic distress [237]. ...
Humans have developed effective survival mechanisms under conditions of nutrient (and energy) scarcity. Nevertheless, today, most humans face a quite different situation: excess of nutrients, especially those high in amino-nitrogen and energy (largely fat). The lack of mechanisms to prevent energy overload and the effective persistence of the mechanisms hoarding key nutrients such as amino acids has resulted in deep disorders of substrate handling. There is too often a massive untreatable accumulation of body fat in the presence of severe metabolic disorders of energy utilization and disposal, which become chronic and go much beyond the most obvious problems: diabetes, circulatory, renal and nervous disorders included loosely within the metabolic syndrome. We lack basic knowledge on diet nutrient dynamics at the tissue-cell metabolism level, and this adds to widely used medical procedures lacking sufficient scientific support, with limited or nil success. In the present longitudinal analysis of the fate of dietary nutrients, we have focused on glucose as an example of a largely unknown entity. Even most studies on hyper-energetic diets or their later consequences tend to ignore the critical role of carbohydrate (and nitrogen disposal) as (probably) the two main factors affecting the substrate partition and metabolism.
... Miniature swine fed a high-fat, high-fructose corn syrup, highcholesterol diet for 10 weeks demonstrated reduced insulinstimulated Akt signalling in the prefrontal cortex . Further, hamsters and wildtype mice display reduced hippocampal and cortex insulin signalling when fed either an SFA and sucrose diet (Mielke et al. 2006) or sweetened water (60% fructose or sucrose) (Mielke et al. 2005). In addition to reduced insulin signalling with sweetened water, mouse models of AD exhibit exacerbated memory deficits and amyloidosis (Cao et al. 2007). ...
With the world’s population aging at a rapid rate, the prevalence of Alzheimer’s disease (AD) has significantly increased. These statistics are alarming given recent evidence that a third of dementia cases may be preventable. The role of lifestyle factors, such as diet and exercise, can directly alter the risk of disease development. However, an understanding of the effectiveness of dietary patterns and exercise strategies to reduce AD risk or improve brain function is not fully understood. The aim of this review is to discuss the effects of diet and exercise on AD risk. Key components of the Western and Mediterranean diets are discussed in relation to AD progression, as well as how physical activity promotes brain health. Components of the Western diet (saturated fatty acids and simple carbohydrates) are detrimental to the brain, impair cognition, and increase AD pathologies. While components of the Mediterranean diet (polyunsaturated fatty acids, polyphenols, and antioxidants) are considered to be neuroprotective. Exercise can significantly reduce the risk of AD; however, specific exercise recommendations for older adults are limited and optimal intensity, duration, and type remains unknown. This review highlights important modifiable risk factors for AD and points out potential avenues for future research.
Novelty Diet and exercise are modifiable factors that can improve brain health and reduce the risk of AD. Polyunsaturated fatty acids, polyphenols, and antioxidants are neuroprotective. Exercise reduces neuroinflammation, improves brain insulin sensitivity, and increases brain derived neurotrophic factor.
... There are limited studies on cognition in diet and/STZ induced rodent models of T2DM; the majority of studies have been conducted in rodents with genetic mutations. However, studies using models of obesity Cordner and Tamashiro, 2015) and T1-and T2DM (reviewed in report memory deficits in hippocampus dependent spatial memory tested in water maze, radial arm maze and object recognition task, with more consistent deficits in diet-induced models (Mielke et al., 2006;. In STZ induced diabetic rats (Sasaki-Hamada et al., 2012;Kalalian-Moghaddam et al., 2013;Thomas et al., 2013) and HF diet induced obesity (Woo et al., 2013;Liu et al., 2015), a deficit is observed in CA1 of the hippocampus and is accompanied by downregulation of insulin signalling (Grillo et al., 2011;Liu et al., 2015). ...
Following aging, type 2 Diabetes Mellitus (T2DM) is the most important risk factor of developing Alzheimer’s disease (AD). It is a metabolic disorder characterised by hyperglycemia and insulin resistance that develops in middle age and is promoted largely by obesity. In this study, we used a T2DM rat model to assess the potential impact T2DM may have on the development of AD. Rats were fed cafeteria-style diet (CD) coupled with low dose injections of Streptozotocin (STZ)(STZ-CD). We found that STZ-CD treated rats showed classic signs of T2DM and a modest deficit in consolidation of spatial recognition memory. In order to mimic the development of early stage AD, half of the rats were infused with a soluble oligomeric amyloid beta (Aβ), which alone was not sufficient to induce long-lasting memory deficits. Interestingly, the T2DM phenotype exacerbated the memory deficits induced by Aβ infusion by prolonging these deficits. Environmental enrichment during a critical two-week period following infusion of Aβ rescued memory deficits induced by Aβ and/or STZ-CD treatment; however, this was time-limited. Biochemical analyses were conducted mainly in proteins involved in the PI3K-Akt signalling pathway and markers of AD and T2DM in CA1 of the hippocampus. Aβ alone induced few long-lasting changes; T2DM phenotype alone induced some changes that were largely mediated by CD treatment alone; however, the majority of dysfunctional regulation of proteins was observed in rats showing a T2DM phenotype that were infused with Aβ. More importantly, many of these changes are similar to those reported in brains of AD patients or rodent models of the disease; notably key proteins in the PI3K-Akt signaling pathway that mediate functions such as autophagy, inflammation and markers of AD. Dysregulation of these proteins may contribute to the long-lasting memory deficits seen in this model, which may provide evidence of molecular mechanisms induced by T2DM that could promote a dysfunctional neuronal environment favouring the development of early stages of Alzheimer’s disease.
... Insulin is known to have important effects on neurotransmission (Matsuzaki et al., 2010). Insulin receptors are highly enriched in synaptosomes (Lomniczi and Ojeda, 2009), are colocalized with the axon terminal markers synaptophysin and synapsin 1 (Mielke et al., 2006), and are found in PSD fractions where they may interact with scaffolding proteins shank and PSD-95 via the insulin receptor tyrosine kinase substrate, IRSp53 (Boeckers et al., 2002). ...
Purpose
Recently, much attention has been devoted to the effects of nutrient-related signals on brain development and functions. Particularly, the dynamics of synaptic gain and loss are fundamental to healthy brain function. Understanding perturbations of these dynamics in neurodegenerative diseases such as Alzheimer’s disease (AD) is of paramount importance in order to devise preventative strategies.
Methods
Scientific studies related to the use of high fat diet (HFD) in adult rodents have been reviewed. A focus has been placed on studies pertinent to the following: (1) the ability of HFD to induce obesity or insulin resistance and (2) alterations in the levels of proteins that are critical for synaptic plasticity of the hippocampus. Studies related to polyphenol or PUFA or studies that used whole brain have been excluded. The effect of obesity on the cellular and molecular mechanisms that underlie hippocampus synaptic plasticity in context of learning, memory and mood have been considered.
Key findings
Out of 80 studies, 11 of them fit the criteria. All 11 studies demonstrate induced obesity in association with impairment of memory function and mood change following feeding rodents HFD. The cellular and molecular mechanisms of these robust effects are discussed herein.
Conclusion
Studies highlight the importance of HFD, not only in influencing obesity, but also in altering cognitive abilities of organisms through changing synapse plasticity without directly causing a pathologic condition such as diabetes. They also lead to the hypothesis that diet can be utilized in preventing the initiation of AD or, in conjunction with pharmaceutical intervention, in treating of AD or in reducing the progression of the disease.
... Studies with diets consisting of ≥ 40% of kilocalories from fat report diet-induced cognitive impairment in both mice and rats (Fu et al., 2017;Underwood and Thompson, 2016;Wang et al., 2016b). In contrast, some studies demonstrate that HFD does not correlate with cognitive impairment (Kosari et al., 2012;Li et al., 2013;Mielke et al., 2006). The impact of HFD in preclinical models on cognitive function has been extensively reviewed (Cordner and Tamashiro, 2015). ...
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.
... There were no significant effects of our diet or drug manipulations on anxiety-like behavior in EPM, depressive-like behavior in forced swim, or on contextual fear conditioning. Though a number of studies demonstrated cognitive impairments after HFD exposure [120][121][122][123][124], others did not [125][126][127][128]. The age at which rodents are exposed to diet-induced obesity may be a factor. ...
Background:
Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer's disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity.
Methods:
Male C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints.
Results:
Peripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures.
Conclusions:
These results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals.
... Spatial memory was significantly increased in the MWM in the CR group and significantly decreased in the high-calorie (HC) group demonstrating that long-term high caloric intake induces autophagy in the hippocampus, which may increase risk to cognitive impairments (Dong et al., 2015). Mielke et al. (2006), on the other hand, found that HFD did not affect spatial memory in the MWM. Other authors have questioned whether cognitive impairment precedes obesity or is a consequence of obesity (Gurung et al., 2016). ...
Obesity continues to be one of the major public health problems due to its high prevalence and co-morbidities. Common co-morbidities not only include cardiometabolic disorders but also mood and cognitive disorders. Obese subjects often show deficits in memory, learning and executive functions compared to normal weight subjects. Epidemiological studies also indicate that obesity is associated with a higher risk of developing depression and anxiety, and vice versa. These associations between pathologies that presumably have different etiologies suggest shared pathological mechanisms. Gut microbiota is a mediating factor between the environmental pressures (e.g., diet, lifestyle) and host physiology, and its alteration could partly explain the cross-link between those pathologies. Westernized dietary patterns are known to be a major cause of the obesity epidemic, which also promotes a dysbiotic drift in the gut microbiota; this, in turn, seems to contribute to obesity-related complications. Experimental studies in animal models and, to a lesser extent, in humans suggest that the obesity-associated microbiota may contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and its comorbidities. These include dysregulation of the HPA-axis with overproduction of glucocorticoids, alterations in levels of neuroactive metabolites (e.g., neurotransmitters, short-chain fatty acids) and activation of a pro-inflammatory milieu that can cause neuro-inflammation. This review updates current knowledge about the role and mode of action of the gut microbiota in the cross-link between energy metabolism, mood and cognitive function.
... The fat fed animals had significantly lower motivation to 'work' for a reward and total movement during trials. 24 Thus, a single behavior task may not be enough to evaluate the various impacts diet can have on the brain. ...
Objectives:
The purpose of the current study is to directly compare a diet high in fat with a diet high in fructose. This side-by-side comparison will allow us to determine the physiological and behavioral effects resulting from the consumption of a diet dominated by one macronutrient.
Methods:
Rats were fed pelletized food containing either 60% fat or 55% fructose diet, or control chow (5.8% kcal of fat, 44.3% kcal carb) for 9 weeks. Animals performed a classic Morris Water Maze (MWM) and a reversal MWM to assess spatial and working memory near the end of the feeding period. At termination, tissue samples were collected including trunk blood, livers, fat pads, and brain punches.
Results:
Animals maintained on the high-fat diet weighed more by the end of the feeding period, had a higher percent body weight change and had higher fat pad weight than the high-fructose and control group. The high-fructose group had higher serum insulin levels than the high-fat group and higher total triglycerides than control or high-fat groups. Additionally, the high-fructose group entered the target quadrant significantly less than high-fat fed animals in the reverse MWM task.
Discussion:
These data suggest that fat accumulation and weight gain are influenced by the high-fat component of the Western-style diet. However, insulin resistance and elevated serum triglycerides are impacted more by high levels of fructose in the diet. Comparative data between a high-fat and high-fructose diet in a single study are novel and shed light on two of the individual components of a Western-style diet.
... Studies have characterized diet-induced learning deficits in hippocampal-dependent long term memory formation (assessed in the radial-arm maze or Morris water maze) when high fat diet consumption began during the juvenile/adolescent period in both rats (Greenwood and Winocur, 2005) and mice (Valladolid-Acebes et al., 2011). This memory impairment was not observed when diet access started in 8 week old rodents (P56; Mielke et al., 2006;White et al., 2009;McNeilly et al., 2011), which is considered to be the end of adolescence in rodents. ...
Adolescence poses as both a transitional period in neurodevelopment and lifestyle practices. In particular, the developmental trajectory of the prefrontal cortex (PFC), a critical region for behavioral control and self-regulation, is enduring, not reaching functional maturity until the early 20 s in humans. Furthermore, the neurotransmitter dopamine is particularly abundant during adolescence, tuning the brain to rapidly learn about rewards and regulating aspects of neuroplasticity. Thus, adolescence is proposed to represent a period of vulnerability towards reward-driven behaviors such as the consumption of palatable high fat and high sugar diets. This is reflected in the increasing prevalence of obesity in children and adolescents as they are the greatest consumers of “junk foods”. Excessive consumption of diets laden in saturated fat and refined sugars not only leads to weight gain and the development of obesity, but experimental studies with rodents indicate they evoke cognitive deficits in learning and memory process by disrupting neuroplasticity and altering reward processing neurocircuitry. Consumption of these high fat and high sugar diets have been reported to have a particularly pronounced impact on cognition when consumed during adolescence, demonstrating a susceptibility of the adolescent brain to enduring cognitive deficits. The adolescent brain, with heightened reward sensitivity and diminished behavioral control compared to the mature adult brain, appears to be a risk for aberrant eating behaviors that may underpin the development of obesity. This review explores the neurodevelopmental changes in the PFC and mesocortical dopamine signaling that occur during adolescence, and how these potentially underpin the overconsumption of palatable food and development of obesogenic diet-induced cognitive deficits.
... Indeed, reduced cognitive performance following consumption of a high fat (HF)diet has been observed in humans [7][8][9][10] and animals [11][12][13][14]. Mechanisms likely involved in diet-induced damage to the brain include impaired glucoregulation [15], increased oxidative stress, and increased inflammation in brain tissue [16][17][18][19]. Previous work from our laboratory provided evidence for impairment of cognitive function in rats fed a high fat high cholesterol (HFHC) diet, and suggested that alterations in the blood-brain barrier (BBB) and in microglial activation may contribute to the reduced spatial and working memory observed [12,20,21]. ...
... In the present study, we used the Morris water maze test for the estimation of cognitive function, because this test has been recognized as a robust and reliable test that is strongly correlated with hippocampal synaptic plasticity and N-methyl-D-aspartate receptor function. 34 As is consistent with previous reports by us 23 and others, 35 the present study showed that short-term high-fat-diet intake did not significantly cause cognitive impairment and brain injury in wild-type mice. On the other hand, the same short-term consumption of high-fat diet significantly enhanced cognitive impairment in 5XFAD mice, as shown by the Morris water maze test. ...
Background
The high‐fat Western diet is postulated to be associated with the onset and progression of Alzheimer's disease (AD). However, the role of high‐fat‐diet consumption in AD pathology is unknown. This study was undertaken to examine the role of high‐fat‐diet intake in AD.
Methods and Results
5XFAD mice, a useful mouse model of AD, and control wild‐type mice were fed (1) high‐fat diet or (2) control diet for 10 weeks. The effects on cerebral AD pathology, cognitive function, and metabolic parameters were compared between each group of mice. High‐fat diet significantly enhanced cerebrovascular β‐amyloid (Aβ) deposition (P<0.05) and impaired cognitive function (P<0.05) in 5XFAD mice, but not in wild‐type mice. High‐fat diet enhanced hippocampal oxidative stress (P<0.05) and NADPH oxidase subunits, gp91phox (P<0.01) and p22phox (P<0.01) in 5XFAD mice, but not in wild‐type mice. Furthermore, high‐fat diet reduced cerebral occludin (P<0.05) in 5XFAD mice, but not in wild‐type mice. Thus, 5XFAD mice exhibited greater susceptibility to high‐fat diet than wild‐type mice regarding cerebrovascular injury and cognitive impairment. On the other hand, 5XFAD mice fed high‐fat diet exhibited much less increase in body weight, white adipose tissue weight, and adipocyte size than their wild‐type counterparts. High‐fat diet significantly impaired glucose tolerance in wild‐type mice but not in 5XFAD mice. Thus, 5XFAD mice had much less susceptibility to high‐fat‐diet‐induced metabolic disorders than wild‐type mice.
Conclusions
High‐fat diet, independently of metabolic disorders, significantly promotes the progression of AD‐like pathology through enhancement of cerebral amyloid angiopathy and oxidative stress.
... Obesity is associated with deficits in visuospatial skills, which are hippocampus-dependent tasks [8]. Studies on the effects of a high-fat diet on cognition in rodents have been inconclusive, with most reports describing significant effects of high-fat dietinduced obesity on performance in the Morris water maze and others failing to detect any differences in spatial learning in this task [14]. We did not find spatial deficits in the VHF group of rats in the current study. ...
Synthetic glucocorticoids are frequently used in clinical practice for treating pregnant women at risk of preterm delivery, but their long-term effects on the infant brain are largely unknown. Pregnant Sprague-Dawley rats were administered vehicle or dexamethasone between gestational days 14 and 21. Male offspring were then weaned onto either a standard chow or a high-fat diet. The postnatal levels of insulin-like growth factor I (IGF-1), tumor necrosis factor-α (TNF-α), and asymmetric dimethylarginine (ADMA) in the plasma, liver, and brain were examined, as well as the possible effects of prenatal dexamethasone on cognition. We found that a postnatal high-fat diet led to spatial deficits detected by the Morris water maze in adult offspring administered dexamethasone prenatally. The spatial deficit was accompanied by decreased IGF-1 mRNA and increased ADMA levels in the dorsal hippocampus. In peripheral systems, a postnatal high-fat diet resulted in decreased plasma IGF-1, increased plasma corticosterone, increased concentrations of transaminases, TNF-α mRNA, and ADMA in the liver, and associated obesity in adult offspring administered prenatal dexamethasone. In conclusion, a postnatal high-fat diet led to spatial deficits, obesity, and altered levels of IGF-1, TNF-α, and ADMA in the plasma, liver, or brain.
... They suggest that the early life period is particularly sensitive to the adverse effects of HFD on cognitive functioning (Boitard et al., 2012). Further rodent studies have described deficits in hippocampal-dependent memory, when HFD exposure started at three to four weeks of age and lasted at least two to three months (Greenwood & Winocur, 2005; Valladolid-Acebes et al., 2011) but not when initiated after eight weeks of age (McNeilly, Williamson, Sutherland, Balfour, & Stewart, 2011; Mielke et al., 2006; White et al., 2009). However, a very long duration of HFD (Farr et al., 2008) or a combination of HFD with high sucrose intake (Kanoski & Davidson, 2010; Molteni, Barnard, Ying, Roberts, & Gomez-Pinilla, 2002; Stranahan et al., 2008) during adulthood have been shown to impair cognition. ...
... to hippocampal-dependent memory (Greenwood and Winocur, 2005). A longitudinal study (Mielke et al., 2006) examining the effects of a Western-style diet on associative learning, found mice who were fed a Western-style diet for one year showed impaired performance in learning an operant bar-pressing task in comparison to those mice fed a control diet. Furthermore, results of this study revealed that mice on Western diet maintenance for one year exhibited increased insulin resistance and weight gain, impairment in glucoregulation, and reduced insulin-mediated signalling in the hippocampus. ...
... to hippocampal-dependent memory (Greenwood and Winocur, 2005). A longitudinal study (Mielke et al., 2006) examining the effects of a Western-style diet on associative learning, found mice who were fed a Western-style diet for one year showed impaired performance in learning an operant bar-pressing task in comparison to those mice fed a control diet. Furthermore, results of this study revealed that mice on Western diet maintenance for one year exhibited increased insulin resistance and weight gain, impairment in glucoregulation, and reduced insulin-mediated signalling in the hippocampus. ...
... Insulin resistance is another risk factor assumed to play a key role in the relationship between the Western diet and age-related cognitive dysfunction, particularly in relation to hippocampal-dependent memory (Greenwood & Winocur, 2005). A longitudinal study (Mielke et al., 2006) examining the effects of a Western-style diet on associative learning, found mice who were fed a Western-style diet for one year showed impaired performance in learning an operant bar-pressing task in comparison to those mice fed a control diet. Furthermore, results of this study revealed that mice on Western diet maintenance for one year exhibited increased insulin resistance and weight gain, impairment in glucoregulation, and reduced insulin-mediated signalling in the hippocampus. ...
The rise in the ageing population has resulted in increased incident rates of cognitive impairment and dementia. The subsequent financial and societal burden placed on an already strained public health care system is of increasing concern. Evidence from recent studies has revealed modification of lifestyle and dietary behaviours is, at present, the best means of prevention. Some of the most important findings, in relation to the Mediterranean diet (MedDiet) and the contemporary Western diet, and potential molecular mechanisms underlying the effects of these two diets on age-related cognitive function, are discussed in this review. A major aim of this review was to discuss whether or not a MedDiet intervention would be a feasible preventative approach against cognitive decline for older adults living in Western countries. Critical appraisal of the literature does somewhat support this idea. Demonstrated evidence highlights the MedDiet as a potential strategy to reduce cognitive decline in older age, and suggests the Western diet may play a role in the aetiology of cognitive decline. However, strong intrinsic Western socio-cultural values, traditions and norms may impede on the feasibility of this notion.
... Mice on HFD showed relatively unimpaired cognitive performance when compared to mice on CD. Our results are consistent with other studies showing no cognitive impairments in mice and rats exposed to HFD and tested for spatial learning in the Morris water maze at various ages [31][32][33]. However, other studies using the T-maze to assess spatial learning and memory retention have observed HFD-induced cognitive impairments [11,16]. ...
Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.
... Only a few studies have reported no change in Morris Water Maze performance after HF diet consumption. In one, mice were exposed to 45% HF diet for 5 or 10 months [28]. In another, 24% HF exposure impaired performance of juvenile but not adult rats [29], and in two additional studies, rats were fed diets enriched with polyunsaturated fatty acids (PUFAs), which had been expected to improve cognitive function [30,31]. ...
The associations between consumption of a high-fat or 'Western' diet and metabolic disorders such as obesity, diabetes, and cardiovascular disease have long been recognized and a great deal of evidence now suggests that diets high in fat can also have a profound impact on the brain, behavior, and cognition. Here, we will review the techniques most often used to assess learning and memory in rodent models and discuss findings from studies assessing the cognitive effects of high-fat diet consumption. The review will then consider potential underlying mechanisms in the brain and conclude by reviewing emerging literature suggesting that maternal consumption of a high-fat diet may have effects on the learning and memory of offspring.
Copyright © 2015. Published by Elsevier Inc.
... Long Evans rats that were supplemented with Crisco showed impairment in the water maze on Day 1 of testing after 5 weeks (Jurdak et al., 2008). Mice fed 45% fat for 12 months, however, showed no significant deficits in the water maze at 5 and 10 months (Mielke et al., 2006). Interestingly, mice fed 33% fat, in the form of lean ground beef, showed better long-and short-term memory than those on 12% fat (Li et al., 2009). ...
Western diets are high in fat and sucrose and can influence behavior and gut microbiota. There is growing evidence that altering the microbiome can influence the brain and behavior. This study was designed to determine whether diet-induced changes in the gut microbiota could contribute to alterations in anxiety, memory or cognitive flexibility. Two month old, male C57BL/6 mice were randomly assigned high fat (42% fat, 43% carbohydrate (CHO), high sucrose (12% fat, 70% CHO (primarily sucrose) or normal chow (13% kcal fat, 62% CHO) diets. Fecal microbiome analysis, step-down latency, novel object and novel location tasks were performed prior to and two weeks after diet change. Water maze testing for long- and short-term memory and cognitive flexibility was conducted during weeks 5-6 post-diet change. Some similarities in alterations in the microbiome were seen in both the high fat and high sucrose diets (e.g., increased Clostridiales), as compared to the normal diet, but the percentage decreases in Bacteroidales were greater in the high sucrose diet mice. Lactobacillales was only significantly increased in the high sucrose diet group and Erysipelotrichales was only significantly affected by the high fat diet. The high sucrose diet group was significantly impaired in early development of a spatial bias for long-term memory, short-term memory and reversal training, compared to mice on normal diet. An increased focus on the former platform position was seen in both high sucrose and high fat groups during the reversal probe trials. There was no significant effect of diet on step-down, exploration or novel recognitions. Higher percentages of Clostridiales and lower expression of Bacteroidales in high-energy diets were related to the poorer cognitive flexibility in the reversal trials. These results suggest that changes in the microbiome may contribute to cognitive changes associated with eating a Western diet.
Copyright © 2015. Published by Elsevier Ltd.
... Histomorphological assessment of brain morphology revealed that prediabetic HFD-treated mice presented similar brain weights as well as cortical and hippocampal areas (Ramos-Rodriguez et al., 2013) and thickness (Ramos-Rodriguez et al., 2014) when compared to untreated mice. These data are in accordance with previous studies on HFD-treated mice with preserved hippocampal synaptic function and long-term potentiation (Mielke et al., 2006). A similar profile was observed in prediabetic db/db mice, since no signifcant differences were observed at 4 weeks of age, when T2D has not debuted yet. ...
Type 2 diabetes (T2D) is an important risk factor for developing dementias, including Alzheimer's disease (AD). Hyperinsulinemia and glucose intolerance, as features of T2D, might increase the neurodegeneration process, synaptic loss and brain atrophy, leading to cognitive impairment observed in AD. Also, adult neurogenesis seems to be impaired in AD models. Therefore, we have studied morphological alterations, cell proliferation and neurogenesis in the central nervous system (CNS) from a classical model of T2D, the db/db mouse, and in a prediabetes insulin-resistant model, obtained after long-term high fat diet (HFD) administration to C57Bl/6 mice. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. Neurogenesis and cell proliferation were increased in young db/db mice, when compared with control mice, whereas no differences were detected in the prediabetic model. We also detected significant correlations between metabolic parameters and central atrophy, altered proliferation and neurogenesis in the central nervous system. Altogether these data support that glycaemia control in elderly patients, could help to control central alterations and improve dementia prognosis.
... It has now become apparent that peripheral changes, particularly those associated with T2DM, energy metabolism, insulin and glucose levels, can contribute to cognitive decline in aging. In fact, metabolic syndrome, which is characterized by the clustering of insulin resistance, hyperglycemia and dyslipidemia, has been recognized to be an important risk factor for the development of cognitive decline in aging and AD (Mielke et al., 2006;Whitmer et al., 2007; Monte and Wands, 2008;Whitmer et al., 2008;Huffman and Barzilai, 2009;Cheng et al., 2012;Yaffe et al., 2012;Craft et al., 2013;Biessels and Reijmer, 2014;Yarchoan and Arnold, 2014). In addition, glucose intolerance and insulin resistance are associated with varying degrees of cognitive and memory deficits, and aging is known to worsen the impact of T2DM on cognitive function. ...
In recent years, childhood overweight and obesity have become a universal public health problem. Obesity may lead to cognitive disorders, depression and anxiety by affecting neuronal processes. Spirulina platensis (SP), a species of microalgae from the Chlorophyceae green algae class, has neuroprotective effects and may reduce body weight. In this study, we aimed to investigate the effects of SP on behavior alongside the role of leptin and Sirtuin-1 in fed with high-fat diet (HFD) adolescent rats. Four-week-old Sprague Dawley male rats were divided into four groups: control, HFD, HFD + SP150 (150 mg/kg/day SP, orally), HFD + SP450 (450 mg/kg/day SP, orally). Rats except for the control group exposed to 60% HFD along 12 weeks. Last 6 weeks SP or vehicle administered. After the behavioral tests, leptin and Sirtuin-1 levels in prefrontal cortex and hippocampus regions were evaluated. SP150 significantly reduced body weight compared with HFD group. The time spent in the center of open field increased significantly in SP150-treated rats compared with HFD. SP150 and SP450 significantly decreased immobility time in forced swim test compared with HFD. Leptin levels in HFD group were significantly lower in prefrontal cortex compared to control group. Leptin levels of the HFD + SP450 group were significantly higher than HFD group in the hippocampus. There was no significant difference between groups in Sirtuin-1 levels. In conclusion, SP supplementation in adolescence period might positively affect chronic high fat-induced anxiety-like and depressive-like behavior by partially affecting brain leptin levels and without affecting Sirtuin-1 levels.
Background:
Obese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice.
Methods:
Obesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9-10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze).
Results:
UCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA.
Conclusions:
DHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.
The ‘apple-shaped’ anatomical pattern that accompanies visceral adiposity increases risk for multiple chronic diseases, including conditions that impact the brain, such as diabetes and hypertension. However, distinguishing between the consequences of visceral obesity, as opposed to visceral adiposity-associated metabolic and cardiovascular pathologies, presents certain challenges. This review summarizes current literature on relationships between adipose tissue distribution and cognition in preclinical models and highlights unanswered questions surrounding the potential role of tissue- and cell type-specific insulin resistance in these effects. While gaps in knowledge persist related to insulin insensitivity and cognitive impairment in obesity, several recent studies suggest that cells of the neurovascular unit contribute to hippocampal synaptic dysfunction, and this review interprets those findings in the context of progressive metabolic dysfunction in the CNS. Signalling between cerebrovascular endothelial cells, astrocytes, microglia, and neurons has been linked with memory deficits in visceral obesity, and this article describes the cellular changes in each of these populations with respect to their role in amplification or diminution of peripheral signals. The picture emerging from these studies, while incomplete, implicates pro-inflammatory cytokines, insulin resistance, and hyperglycemia in various stages of obesity-induced hippocampal dysfunction. As in the parable of the five blind wanderers holding different parts of an elephant, considerable work remains in order to assemble a model for the underlying mechanisms linking visceral adiposity with age-related cognitive decline.
This article is part of the special Issue on ‘Cross Talk between Periphery and the Brain’.
Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.
This article is part of the special Issue on ‘Cross Talk between Periphery and the Brain’.
Consumption of high-fat diets (HFD) has been associated with neuronal plasticity deficits and cognitive disorders linked to the alteration of glutamatergic disorders in the hippocampus. As young individuals are especially vulnerable to the effects of nutrients and xenobiotics on cognition, we studied the effect of chronic consumption of saturated (SOLF) and unsaturated oil-enriched foods (UOLF) on: i) spatial memory; ii) hippocampal synaptic transmission and plasticity; and iii) gene expression of glutamatergic receptors and hormone receptors in the hippocampus of adolescent and adult mice. Our results show that both SOLF and UOLF impair spatial short-term memory. Accordingly, hippocampal synaptic plasticity mechanisms underlying memory, and gene expression of NMDA receptor subunits are modulated by both diets. On the other hand, PPARγ gene expression is specifically down-regulated in adolescent SOLF individuals and up-regulated in adult UOLF mice.
Obesity is a complex disease that is the result of a number of different factors including genetic, environmental, and endocrine abnormalities. Given that monogenic forms of obesity are rare, it is important to identify other mechanisms that contribute to its etiology. Methyl-Cp-G binding protein 2 (MeCP2) is a neuroepigenetic factor that binds to methylated regions of DNA to influence transcription. Past studies demonstrate that disruption in MeCP2 function produces obesity in mice. Using a diet-induced obesity mouse model, we show that perinatal exposure to high fat diet significantly decreases MeCP2 protein expression in the hypothalamus of female mice, effects not seen when high fat diet is given to mice during adulthood. Moreover, these effects are seen specifically in a subregion of the hypothalamus known as the arcuate nucleus with females having decreased MeCP2 expression in rostral areas and males having decreased MeCP2 expression in intermediate regions of the arcuate nucleus. Interestingly, mice gain more weight when exposed to high fat diet during adulthood relative to mice exposed to high fat diet perinatally, suggesting that perhaps high fat diet exposure during adulthood may be affecting mechanisms independent of MeCP2 function. Collectively, our data demonstrate that there are developmentally sensitive periods in which MeCP2 expression is influenced by high fat diet exposure and this occurs in a sexually dimorphic manner.
It has been well recognized that intake of diets rich in saturated fats could result in development of metabolic disorders such as type 2 diabetes mellitus, obesity and cardiovascular diseases. Recent studies have suggested that intake of high fat diet (HFD) is also associated with cognitive dysfunction. Various preclinical studies have demonstrated the impact of short and long term HFD feeding on the biochemical and behavioural alterations. This review summarizes studies and the protocols used to assess the impacts of HFD feeding on cognitive performance in rodents. Further, it discuss the key mechanisms that are altered by HFD feeding, such as, insulin resistance, oxidative stress, neuro-inflammation, transcriptional dysregulation and loss of synaptic plasticity. Along with these, HFD feeding also alters the vascular components of brain such as loss of BBB integrity and reduced cerebral blood flow. It is highly possible that these factors are responsible for the development of cognitive deficits as a result of HFD feeding.
L’obésité, considérée comme pandémique, est associée à l’apparition de troubles cognitifs et émotionnels chez l’Homme comme chez l’animal. La prévalence de l’obésité augmente de manière drastique chez les enfants et les adolescents. Or l’adolescence est une période primordiale pour la maturation des structures cérébrales (notamment l’hippocampe et l’amygdale) qui vont sous-tendre les processus cognitifs pour le restant de la vie de l’individu. Cependant, aucune étude n’avait investigué la potentielle vulnérabilité de cette période développementale aux effets de l’obésité sur la mémoire, comparativement à l’âge adulte. Nous avons donc effectué cette comparaison chez le rongeur, en modélisant l’obésité par une exposition à un régime hyper-lipidique (HL) pendant une période incluant l’adolescence versus à l’âge adulte uniquement (i.e. excluant l’adolescence). Nous mettons en évidence que l’obésité induite à l’adolescence provoque des altérations mnésiques, qui ne sont pas retrouvés lorsque l’obésité est induite à l’âge adulte. La majorité des études sur les effets de l’obésité ayant mis en évidence une altération des mémoires dépendantes de l’hippocampe, nous nous sommes tout d’abord focalisés sur les fonctions hippocampiques. Nous avons ensuite exploré le système amygdalien, impliqué dans les mémoires émotionnelles et peu étudié dans le cadre de l’obésité. Ces deux systèmes fonctionnels ont été appréhendés au travers d’approches comportementales visant à évaluer les performances mnésiques, mais également d’approches d’imagerie cellulaire et d’électrophysiologie afin d’évaluer la plasticité cellulaire au sein de ces structures. Nous mettons en évidence que l’obésité induite à l’adolescence impacte la mémoire et la plasticité de ces systèmes de manière bidirectionnelle en dégradant les fonctions hippocampiques et en exacerbant les fonctions amygdaliennes. Concernant les mécanismes impliqués dans ces effets nous mettons en évidence l’existence d’une exacerbation de la réponse inflammatoire spécifiquement au niveau de l’hippocampe chez les animaux exposés au régime HL à l’adolescence, ce qui pourrait expliquer les déficits des fonctions hippocampiques. Enfin, nous montrons que la dérégulation de l’axe corticotrope chez ces animaux est responsable des effets comportementaux et cellulaires observés au niveau des fonctions amygdaliennes. L’ensemble de ces résultats montre l’urgence de développer les études sur l’obésité juvénile, dont les effets importants sur les fonctions cognitives et émotionnelles pourraient engendrer une altération importante de la qualité de vie et une prise en charge accrue de ces sujets tout au long de leur vie.
The interaction between meal timing and light regulates circadian rhythms in mammals and not only determines the sleep-wake pattern but also the activity of the endocrine system. Related with that, the necessity to fulfil energy needs is a driving force that requires the participation of cognitive skills whose performance has been shown to undergo circadian variations. These facts have led to the concept that cognition and feeding behaviour can be analysed from a chronobiological perspective. In this context, research carried out during the last two decades has evidenced the link between feeding behaviour/nutritional habits and cognitive processes, and has highlighted the impact of circadian disorders on cognitive decline. All that has allowed to hypothesize a tight relationship between nutritional factors, chronobiology and cognition. In this connection, experimental diets containing elevated amounts of fat and sugar (high-fat diets; HFDs) have been shown to alter in rodents the circadian distribution of meals, and to have a negative impact on cognition and motivational aspects of behaviour that disappear when animals are forced to adhere to a standard temporal eating pattern. In this review we will present relevant studies focussing on the effect of HFDs on cognitive aspects of behaviour, paying particular attention to the influence that chronobiological alterations caused by these diets may have on hippocampal-dependent cognition.
Epidemiological studies showed that a high-fat diet threatened human health seriously. It can induce various diseases, such as obesity, metabolic disturbance and cognitive dysfunction which also related to insulin signaling. In the present study, Aβ1-42 induced AD model mice and normal mice were given a standard diet and high-fat diet, respectively. Meanwhile, Okra polysaccharides were used to treat AD mice to explore the possible mechanism between Alzheimer's disease and insulin signals. Weight and blood glucose of mice were measured weekly. Through the Morris water maze and the novel object recognition test, the Okra polysaccharides could improve the cognitive impairment of the AD mice. In addition, we also performed the serum chemistry analysis of mice, studied the histopathological changes in the hippocampal CA1 region by HE staining and detected the expressions of AKT, PI3K, ERK1/2, and GSK3β in the hippocampus by western blot. These results suggested that a high-fat diet can aggravate the metabolic disorder in AD mice and Okra polysaccharides can significantly reverse the metabolic disorder induced by high-fat diet and cognitive function injury in AD mice.
Cognitive development may be influenced by maternal nutrition especially fats. Indian population is vegetarian and main source of fat is dairy. This study investigates the effect of dairy fat consumption during pregnancy in an animal model on fatty acids, brain neurotrophins (brain derived neurotrophic factor: BDNF; and nerve growth factor: NGF) and cognitive performance in adult offspring. Pregnant Wistar rats were assigned to control (Control C) and four treatment groups: High fat diet (HFD); High fat diet supplemented with omega-3 fatty acids (HFDO); High fat diet deficient in vitamin B12 (HFBD); High fat deficient in vitamin B12 supplemented with omega-3 fatty acids (HFBDO). Half the dams were dissected on d20 of gestation, and the brains of their pups were collected. The remaining dams delivered on d22 of gestation and were assigned to a control diet. The cognitive performance of these adult offspring was assessed at 6 mo of age. Brain fatty acids were comparable to control in the pups at birth and offspring at 6 mo of age. The protein levels of BDNF in the pup brain at birth were lower in both the HFD (p < 0.01) and HFBD (p < 0.05) groups as compared to control. The mRNA levels of TrK B were lower (p < 0.05) in the pup brain at birth in the HFD as compared to control group. In the offspring at 6 mo of age the protein levels of BDNF and NGF in all the treatment groups were similar to that of control. However, the mRNA levels of only BDNF (p < 0.01 for both) were higher in the HFBD group as compared to both control and HFD groups. The cognitive performance of the adult offspring from various dietary groups was similar to control. In conclusion, consumption of a maternal high dairy fat diet although lowered the levels of brain BDNF in the pup at birth it does not affect the cognitive health of the adult offspring.
Type 2 diabetes mellitus (T2DM) is a complex, multifactorial metabolic disease, and the number of patients with T2DM has continued to increase in recent years. Large-scale proteomic studies on animal models of T2DM are of great importance to understand the pathophysiology of T2DM. Therefore, in our study, Isobaric tags for relative and absolute quantification (iTRAQ) and Parallel reaction monitoring (PRM) were used for proteomic analysis of skeletal muscles from T2DM-susceptible and -tolerant Bama mini-pig models induced by a high-fat, high-sugar diet. In our proteomic analysis, a total of 1646 proteins and 13 differentially expressed proteins (DEPs) were identified by iTRAQ-mass spectrometry, and 6 differentially expressed proteins were validated by PRM. Gene Ontology (GO) analysis revealed that most DEPs were extracellular matrix (ECM) proteins and participated in several biological processes, such as negative regulation of JAK-STAT cascade, negative regulation of STAT cascade, roundabout signaling pathway and peptide cross-linking via chondroitin 4-sulfate glycosaminoglycan, and the molecular functions of roundabout binding, glycosaminoglycan binding, heparin binding, sulfur compound binding, collagen binding, and kinase inhibitor activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results showed that the differentially expressed proteins were involved in 14 pathways, including human disease pathways, metabolic pathways, signal transduction pathways, signaling molecules and interaction pathways, and the cellular process pathways associated with phagosomes and focal adhesion. In conclusion, the proteomics based on iTRAQ and PRM in T2DM-susceptible and -tolerant Bama mini-pig models showed that changes in amino acid metabolism, inflammation-associated pathways and the impaired function and environment of extracellular matrix are risk factors associated with increased pathogenesis of T2DM in Bama mini-pig.
Long-term consumption of Western diet, which is enriched in saturated fats, cholesterol, and n-6 fatty acids, produces obesity, insulin resistance, oxidative stress, low-grade inflammation, and cognitive dysfunction due to the generation of high levels of lipid peroxidation products. High levels and long-term presence of lipid peroxidation products, inflammatory mediators, and proinflammatory cytokines are associated with the pathogenesis of age-related chronic visceral and brain diseases. In addition, the presence of high amounts of cholesterol in Western diet results in hypercholesterolemia, which causes hyperphosphorylation of tau protein in the brain. In addition, Western diet contains high levels of sodium chloride (table salt), which increases blood pressure (BP). High BP is an important risk factor for heart disease, kidney diseases, and metabolic syndrome. Metabolic syndrome is an important risk factor for stroke, Alzheimer's disease, and depression. Onset of stroke, Alzheimer's disease, and depression results in neurodegeneration, loss of cognitive function, and long-term disability.
There is growing evidence that over consumption of high-fat foods and insulin resistance may alter hippocampal-dependent cognitive function. To study the individual contributions of diet and peripheral insulin resistance to learning and memory, we used a transgenic mouse line that overexpresses ecto-nucleotide pyrophosphatase phosphodiesterase-1 in adipocytes, which inhibits the insulin receptor. Here, we demonstrate that a model of peripheral insulin resistance exacerbates high-fat diet induced deficits in performance on the Morris Water Maze task. This finding was then reviewed in the context of the greater literature to explore potential mechanisms including triglyceride storage, adiponectin, lipid composition, insulin signaling, oxidative stress, and hippocampal signaling. Together, these findings further our understanding of the complex relationship among peripheral insulin resistance, diet and memory.
The consumption of artificial sweeteners is very popular because they are low in calories. Although, Food and Drug Administration has approved aspartame, acesulfame-k, neotame, cyclamate and alitame for use as per acceptable daily intake value, but it is becoming increasingly evident that breakdown products of these sweeteners may produce harmful metabolic effects in the visceral tissues and brain. Thus, aspartame is hydrolyzed into phenylalanine, aspartic acid, and methanol. Phenylalanine regulates neurotransmitters, whereas aspartic acid plays an important role in inducing excitotoxicity in the brain. Lastly methanol is oxidized into formaldehyde and diketopiperazine, a carcinogen, which mediates a number of other highly toxic effects. In experimental rats saccharin is known to cause bladder cancer. Steviol, a natural extract from the Stevia plant is a mutagen, but the safety of steviol glycoside as well as steviol oxidatives has been proven. Sucralose (Splenda™) is chlorinated sucrose, which is 600 times sweeter than sucrose. Sucralose has been reported to cause dizziness, head and muscle aches, stomach cramps, diarrhea, chronic inflammation and bladder issues in rodents and humans. So far studies performed on the safety of artificial sweeteners have been a major concerned due to their neurological effects and cancer-related issues.
Perturbations of brain energy metabolism are involved in Alzheimer's disease (AD). Adenosine monophosphate-activated kinase (AMPK) is a master energy sensor that monitors the levels of key energy metabolites. Electroacupuncture (EA) has demonstrated therapeutic potential for the treatment of AD. The effects of EA on cognitive functions and the changes of AMPK and its phosphorylated form (p-AMPK) expression were investigated in senescence-accelerated mouse prone 8 (SAMP8) mice. Cognitive function of SAMP8 mice was assessed using Morris water maze test after EA treatment. Then mice were sacrificed for immunohistochemistry and western blot analysis. EA stimulation significantly alleviated memory impairment of AD mice, and increased the levels of p-AMPK in the hippocampus. These results suggest that EA improved cognitive function associated with AMPK activation, AMPK may be a molecular target of EA in treating AD.
Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age = 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
The integral SV (synaptic vesicle) protein synaptophysin was one of the first nerve terminal proteins identified. However its role, if any, in the SV life cycle remains undetermined. One of the most prominent features of synaptophysin is that its cytoplasmic C-terminus largely consists of pentapeptide repeats initiated by a tyrosine residue. Synaptophysin is heavily phosphorylated by tyrosine kinases in the nerve terminal, suggesting that this phosphorylation is central to its function. This review will cover the evidence for tyrosine phosphorylation of synaptophysin and how this phosphorylation may control its function in the SV life cycle.
Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinositol 3-kinase, including
glucose transport, glycogen synthesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase
and these biological responses has been poorly understood. Recently, it has been shown that protein kinase B (PKB/c-Akt/Rac)
lies immediately downstream from phosphatidylinositol 3-kinase. Here, we show that expression of a constitutively active form
of PKB induced glucose uptake, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol
3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB
induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen
synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation
of rapamycin-sensitive serine/threonine kinase by PKB in L6 myotubes might be involved in the enhancement of glycogen synthesis
and protein synthesis, respectively. These results suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase
activation to multiple biological functions of insulin through regulation of downstream kinases in skeletal muscle, a major
target tissue of insulin.
To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT).
Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery.
Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score.
Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association.
We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.
One-month-old rats were fed 1 of 4 high-fat diets (20% fat) or chow (4.5% fat) for 3 months. Dietary saturated (SFA), monounsaturated (MUFA), or polyunsaturated (PUFA) fatty acids varied such that their independent effects on cognitive performance could be tested. Rats were tested on a variable-interval delayed-alternation task. Impairment in both the ability to learn the basic alternation rule and remembering trial-specific information over time was observed in rats fed the experimental diets relative to those fed chow. The degree of impairment was highly associated with the level of SFAs fed and independent of the MUFAs or PUFAs. Dietary fat altered brain phosphatidylcholine fatty-acid profile, but the membrane changes did not correlate with cognitive impairment. The results demonstrate that cognitive impairment is directly associated with SFA intake but suggest that the mechanism is independent of bulk brain membrane compositional changes.
Changes in memory performance were examined after intake of a glucose (50 g) or saccharin (50 mg) solution in fasted men and women. Glucoregulation was estimated by using a recovery index to categorize participants within each gender as having poor or good recovery. Memory was assessed with word-learning tasks in which the imagery-evoking value of the words was systematically manipulated to yield high- and low-imagery lists. The results showed that men and women characterized as having poor glucose regulation had significantly worse memory performance under the saccharin condition. This decrement was reversed by glucose ingestion. These effects were observed for both low- and high-imagery words. This study supports the hypothesis that poor glucoregulation is associated with poor memory performance even in young healthy participants and that the ingestion of glucose can improve their memory.
Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age = 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
PDZ domains are protein-interaction domains that are often found in multi-domain scaffolding proteins. PDZ-containing scaffolds assemble specific proteins into large molecular complexes at defined locations in the cell. In the postsynaptic density of neuronal excitatory synapses, PDZ proteins such as PSD-95 organize glutamate receptors and their associated signalling proteins and determine the size and strength of synapses. PDZ scaffolds also function in the dynamic trafficking of synaptic proteins by assembling cargo complexes for transport by molecular motors. As key organizers that control synaptic protein composition and structure, PDZ scaffolds are themselves highly regulated by synthesis and degradation, subcellular distribution and post-translational modification.
The present review integrates findings of published studies that have evaluated the cognitive function of treated and untreated type 2 diabetic patients and provides a detailed overview of the neuropsychological assessments conducted. Cognitive deficits are observed in older people with glucose intolerance or untreated diabetes but these deficits appear to be attenuated by treatments that improve glycemic control. Cognitive decrements in treated type 2 diabetic patients are most consistently observed on measures of verbal memory (35% of the measures) and processing speed (45% of the measures) while preserved function is observed on measures of visuospatial, attention, semantic and language function. Some studies suggest that deficits in cognitive functions are associated with poorer glycemic control. A number of other factors, such as depression, cardiovascular and cerebrovascular disease, increase these deficits. We conclude that, in diabetic patients who achieve and maintain good glycemic control, type 2 diabetes only has a small impact on cognitive functions before the age of 70 years. However, early onset of type 2 diabetes, poor glycemic control and the presence of micro- and macrovascular disease may interact to produce early cognitive deficits. In older adults (70 years and over), diabetes likely interacts with other dementing processes such as vascular disease and Alzheimer's disease to hasten cognitive decline.
The pancreas is a heterogeneous organ mixed with both exocrine and endocrine cells. The pancreas is involved in metabolic activities with the endocrine cells participating in the regulation of blood glucose, while the exocrine portion provides a compatible environment for the pancreatic islets and is responsible for secretion of digestive enzymes. The purpose of this study was to identify pancreatic proteins that are differentially expressed in normal mice and those with diet-induced type 2 diabetes (T2DM). In this study, C57BL/6J male mice fed a high fat diet became obese and developed T2DM. The pancreatic protein profiles were compared between control and diabetic mice using two-dimensional gel electrophoresis. Differentially expressed protein "spots" were identified by mass spectrometry. REG1 and REG2 proteins, which may be involved in the proliferation of pancreatic beta cells, were up-regulated very early in the progression of obese mice to T2DM. Glutathione peroxidase, which functions in the clearance of reactive oxidative species, was found to be down-regulated in the diabetic mice at later stages. The RNA levels encoding REG2 and glutathione peroxidase were compared by Northern blot analysis and were consistent to the changes in protein levels between diabetic and control mice. The up-regulation of REG1 and REG2 suggests the effort of the pancreas in trying to ameliorate the hyperglycemic condition by stimulating the proliferation of pancreatic beta cells and enhancing the subsequent insulin secretion. The down-regulation of glutathione peroxidase in pancreas could contribute to the progressive deterioration of beta cell function due to the hyperglycemia-induced oxidative stress.
Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(++) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db(++) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.
The hypothesis that dietary fat can influence glucose tolerance and insulin sensitivity adversely or beneficially was tested in rats fed diets supplemented with variable amounts and types of fat. Two concentrations of fat (10% and 20% by weight) diets were prepared and given to male Wistar rats for 5 weeks. The animals supplemented with high fat (20%) diets showed significant increase in body and visceral fat weights as compared to rats fed low fat (10%) diets. Only the rats supplemented with a diet containing 20% butter oil showed impaired glucose tolerance and insulin insensitivity compared to normal rats. However, rats fed olive oil diets had relatively normal glucose tolerance and insulin sensitivity, although they increased body weight and visceral fats in parallel with rats fed butter oil diets. Fish oil conferred protection against obesity induced by olive oil or butter oil diets and also markedly reduced the impairment in glucose tolerance and insulin sensitivity induced by butter oil. In conclusion, these results suggest that diet therapy with fish oil or olive oil may be useful for treatment of patients with impaired glucose tolerance and/or type 2 diabetes.
The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.
In aged rats and humans, impaired glucose regulation has been correlated with poor memory performance, and glucose treatment can result in improved performance. We tested this glucose hypothesis with rats in a 14-unit T-maze that has provided robust evidence of age-related performance decline. Aged (24-25 month) and young (6-7 month) male F-344 rats were pretrained for one-way active avoidance before receiving complex maze training (4 daily trials over 5 days) with the contingency of moving through each of 5 segments to avoid footshock. Ten min before daily training, aged rats received either saline or glucose in doses of 10, 100, or 500 mg/kg IP, while young rats received saline. Significant (ps less than 0.05) age-related increases in errors, runtime, and shock duration were observed. Glucose treatment had no significant effect on the number of maze errors committed; however, performance variables such as runtime and shock duration appeared to be reduced in rats receiving glucose. About 4-6 weeks later, a sample of these rats was fasted overnight, injected IP with glucose (150 mg/kg), and bled at various postinjection intervals to obtain estimates of blood glucose and insulin levels. Significant correlations (ps less than 0.05) were observed between maze errors and baseline glucose levels, r(21) = -.62, and peak glucose response, r(19) = .49. However; within the aged group, significant correlations (ps less than 0.01) with maze errors emerged only for baseline glucose, r(13) = -.69, and peak insulin response, r(13) = -.65. Thus, regulation of insulin, but not glucose, appeared related to learning abilities among aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenoceptor antagonists block the enhancement of memory storage produced by epinephrine injection, but not that produced by glucose injection. The present experiment determined whether adrenoceptor antagonists modify resting blood glucose levels or the magnitude of epinephrine-, glucose-, and footshock-induced increases in circulating glucose levels in a manner related to these previously observed effects on memory. The alpha- and beta-adrenoceptor antagonists, phenoxybenzamine and propranolol, respectively, were injected in rats 30 min prior to administration of epinephrine, glucose, or footshock. Plasma glucose levels were sampled during the next 30 min. Epinephrine-induced increases in plasma glucose levels were potentiated by phenoxybenzamine and were attenuated and delayed by propranolol. The adrenoceptor antagonists did not alter resting plasma glucose levels, or the increases in plasma glucose levels resulting from glucose injection or footshock. These findings suggest that phenoxybenzamine and propranolol alter blood glucose responses to epinephrine injection in a manner which may contribute to attenuation of epinephrine-induced enhancement of memory storage with peripheral injections of adrenoceptor antagonists.
Previous results have suggested that memory processing may involve the sequential activation of subcortical and cortical structures. To study this phenomenon, we have examined the immediate (15 min) and delayed (220 min) metabolic changes produced in BALB/c mice by a partial training session in a bar-pressing appetitive task, using the [14C]-2-deoxyglucose (2-DG) relative glucose uptake method. These relative metabolic changes were compared to the ones produced in several control groups: untrained animals, sham-conditioned animals, overtrained animals, and animals forced to walk on a moving belt (immediate and delayed condition). Animals were given a single intrajugular injection (5 microCi) of 2-DG either 5 min before or 3 h (delayed condition) after the second training session. Forty minutes after the 2-DG injection, the animals were sacrificed and their brains processed for autoradiography. At the 15-min delay, a large 2-DG labeling increase was found in partially trained animals for various subcortical areas (septum, diagonal band, hippocampus, thalamus, and mammillary bodies) while a much smaller increase was found in four cortical areas (frontal, cingulate, parietal, and sensory motor cortices). At the 220-min delay, we observed a large 2-DG labeling increase in cortical (frontal, pyriform, and cingulate cortices) and subicular areas while a moderate 2-DG labeling increase was observed in entorhinal cortex and the diagonal band. These results show that, shortly after training, subcortical structures are preferentially activated while cortical structures are much less activated. Three hours later, at a time when retention performances have been shown to improve spontaneously in the same strain of mice and in the same task, cortical structures are highly activated.
Poor glucose regulation predicts memory deficits in individual elderly humans. The present experiment determined whether glucose
regulation was also related to memory and to sleep in aged rodents. Glucose regulation, inhibitory avoidance, and daytime
sleep were assessed in young (3-month-old) and old (24-month-old) rats. Correlations were obtained between glucose regulation
and the other variables in individual rats. In old rats, the magnitude of increases in blood glucose levels after glucose
injections (500 mg/kg) was inversely correlated with retention of inhibitory avoidance and duration of paradoxical sleep bouts.
In young rats, these measures were not significantly correlated. Because the deficits in sleep and memory in aged rats were
largely confined to those rats with poor glucose control, peripheral glucose regulation may be a useful biological marker
that accompanies cognitive and neurobiological dysfunction during aging.
A semi-synthetic diet containing 20% polyunsaturated fat (soybean) oil was fed to young male hooded rats for 21 days. These animals exhibited improved performance on an environmentally-cued testing paradigm which is thought to reflect cognitive learning skills (i.e., Place Navigation Water Task). Other rats fed the same base diet but containing 20% saturated fat (lard) showed no such improvement compared to chow-fed (4.5% mixed fat) controls. The animals fed soybean oil also exhibited a transient resistance to extinguish this learning. This improved learning could not be explained by changes in general motor activity, basal body temperature, energy consumption, body weight, or in the brain activity of choline acetyltransferase, the marker enzyme for cholinergic neurons. These findings constitute the first evidence that short-term variations in the quality of dietary fat can enhance mammalian learning.
We describe the use of a novel portable blood glucose meter to repetitively and rapidly measure blood glucose levels in mice. We used this apparatus to replicate in the mouse, an insulin tolerance test (ITT) developed for humans. This test involves repeated glucose sampling (0, 1, 3, 5, 7, 10, 15, and 20 min) after an IV bolus of 0.4 IU/Kg of insulin. We first ran comparative tests with a conventional automated glucose analyser to assess the precision and reliability of the blood glucose meter for use in the mouse. High correlation were found between the two measures using either capillary or trunk whole blood. The variability of measurement over five consecutive determinations was about 3%. It was possible to take repetitive measures at about 70 s intervals.
Cognitive impairment is highly prevalent among the elderly. Subjects with disturbed glucose metabolism may be at risk of impaired cognitive function, as these disturbances can influence cognition through atherosclerosis, thrombosis and hypertension. We therefore studied the cross-sectional association of cognitive function with hyperinsulinaemia, impaired glucose tolerance and diabetes mellitus in a population-based cohort of 462 men aged 69 to 89 years. Cognitive function was measured by the 30-point Mini-Mental State Examination. Results were expressed as the rate ratio (95% confidence interval) of the number of erroneous answers given on the Mini-Mental State Examination by the index compared to the reference group. Compared to subjects with normal glucose tolerance, known diabetic patients had a rate ratio of 1.23 (1.04-1.46), newly-diagnosed diabetic patients of 1.16 (0.91-1.48) and subjects with impaired glucose tolerance of 1.18 (0.98-1.41), after adjustment for confounding due to age, occupation and cigarette smoking (p-trend = 0.01). Non-diabetic subjects in the highest compared to the lowest quartile of the area under the insulin curve had a rate ratio of 1.24 (1.03-1.50), after adjustment for confounding (p-trend = 0.02). The results did not change appreciably when potentially mediating factors, including cardiovascular diseases and risk factors associated with the insulin resistance syndrome, were taken into account. These results suggest that diabetes, as well as impaired glucose tolerance and hyperinsulinaemia in non-diabetic subjects are associated with cognitive impairment.
We describe an adjustable food delivery system that cuts and delivers calibrated pieces of spaghetti to be used as reinforcers to train mice in an appetitive bar-pressing task. The food delivery is computer-controlled. Uneaten reinforcers are detected and removed automatically. One main advantage of this system is the ability to adjust reinforcer size to as small as 3 mg. A second advantage is that small reinforcers effectively prevent the rapid satiation usually observed with commercial products designed for rats, and allow for the expression of high behavioral output. Finally, the use of these dustless reinforcers drastically reduces the incidence of blockage, a common occurrence with commercial products using pellets.
Age-related deficits in memory are correlated with deficits in paradoxical sleep and poor glucose tolerance in rats. The present experiment used a longitudinal design to determine whether memory or glucose tolerance in middle-aged rats could predict deficits in memory, sleep, and glucose tolerance in old age. Correlations were obtained between spontaneous alternation scores and glucose tolerance levels in middle age (14 months) and inhibitory avoidance, daytime sleep, and glucose tolerance levels in old age (24 months). Spontaneous alternation scores, but not glucose tolerance levels, predicted performance on all 3 behavioral and biological measures in old age. Measures of functional integrity, such as memory, may be sensitive predictors of subsequent age-related change in specific cognitive and neurobiological systems.
We examined changes in cognitive performance following the intake of a glucose (50 g) or saccharin solution (50 mg) in fasted elderly male and female subjects. Glucoregulation was estimated using a recovery index that was used to categorize subjects within each sex as having poor or good recovery. Elderly males with poor recovery performed worse on the Logical Memory subtest of the Wechsler Memory Scale and on the free recall or recognition parts of a work list task. The item analysis of the Logical Memory subtest showed that male subjects with poor recovery remembered less of the last items of the paragraphs after drinking saccharin while the first items were equally remembered by both groups. Glucose improved the performance of the males with good regulation for the first seven items while the performance of males with poor regulation decreased for those items under glucose. The present study support the notion that peripheral glucoregulation can influence memory performance and that the ingestion of glucose can influence certain aspects of memory functioning.
A high intake of saturated fat and cholesterol and a low intake of polyunsaturated fatty acids have been related to an increased risk of cardiovascular disease. Cardiovascular disease has been associated with dementia. We investigated the association between fat intake and incident dementia among participants, age 55 years or older, from the population-based prospective Rotterdam Study. Food intake of 5,386 nondemented participants was assessed at baseline with a semiquantitative food-frequency questionnaire. At baseline and after an average of 2.1 years of follow-up, we screened for dementia with a three-step protocol that included a clinical examination. The risk of dementia at follow-up (RR [95% CI]) was assessed with logistic regression. After adjustment for age, sex, education, and energy intake, high intakes of the following nutrients were associated with an increased risk of dementia: total fat (RR = 2.4 [1.1-5.2]), saturated fat (RR = 1.9 [0.9-4.0]), and cholesterol (RR = 1.7 [0.9-3.2]). Dementia with a vascular component was most strongly related to total fat and saturated fat. Fish consumption, an important source of n-3 polyunsaturated fatty acids, was inversely related to incident dementia (RR = 0.4 [0.2-0.91), and in particular to Alzheimer's disease (RR = 0.3 [0.1-0.9]). This study suggests that a high saturated fat and cholesterol intake increases the risk of dementia, whereas fish consumption may decrease this risk.
In this series of experiments, we examined the ability of post-training glucose injections to improve memory of the Balb/cAnNCrlBR strain of mice for a bar-pressing task. We could not replicate this effect which has been demonstrated in many other strains of mice including Balb/cbyJ, a related strain. We found that the Balb/cAnNCrlBR strain of mice is also much less sensitive to the disrupting effects produced by pre- or post-training injections of the competitive cholinergic antagonist scopolamine. This strain also shows altered glucoregulation compared to the Balb/cbyJ strain. The absence of glucose effects on memory in Balb/cAnNCrlBR mice appears to be associated with decreased sensitivity to cholinergic antagonists. These results can be contrasted with previous ones obtained in a related strain, the Balb/cbyJ, in which glucose was shown to improve memory while scopolamine could easily disrupt memory processes. Taken together, these data provide additional indirect support for the hypothesis that glucose improvement of memory is closely linked to a functional interaction with central cholinergic systems. The comparison of these two strains could be the basis for a useful animal model to investigate the relationship between age-related changes in memory and central cholinergic function.
As part of a continuing investigation of the relationship between dietary factors and cognitive function, the present study examined the combined effects of environmental influences and high-fat diets on learning and memory. Following 3 months of dietary (20% by weight fat diets, composed primarily of either beef tallow or soybean oil versus standard laboratory chow) and environmental treatments (standard, enriched or impoverished), subjects were tested on a variable interval delayed alternation (VIDA) task which measures learning and memory functions that differentially involve specific brain regions. The results confirmed the negative effects of high fat diets, relative to chow, on all aspects of VIDA performance and showed that environmental enrichment overcame deficits associated with dietary fat. Housing rats fed high-fat diets in an impoverished environment did not further exacerbate cognitive deficits observed in such rats living under standard conditions. By comparison, chow-fed rats exhibited no benefit associated with the enriched environment on any aspect of task performance, and only a transitory learning impairment when housed in an impoverished environment. The results show that high fat diets and environmental conditions influence cognitive function and that these two factors interact with one another to produce different profiles of benefits and impairments.
A major focus of aging research has been the search for treatments that will prevent or ameliorate the memory deficits associated with aging. One paradigm, lifelong caloric restriction, has been reported to reduce some of the effects of aging. In the current report, we examined the effects of this treatment on age-related deficits in LTP, a putative cellular building block for memory formation. We report here that lifelong caloric restriction completely prevents the age-related deficit in LTP. In addition, we report that there is a dramatic decrease in the expression of the NMDA receptor subunit NR1 in aged rats and this age-related defect is also prevented by caloric restriction. These data provide a molecular and cellular mechanism by which life long caloric restriction may ameliorate some of the cognitive deficits associated with the aging process.
The association of obesity with type 2 diabetes has been recognized for decades, and the major basis for this link is the ability of obesity to engender insulin resistance. Insulin resistance is a fundamental aspect of the etiology of type 2 diabetes and is also linked to a wide array of other pathophysiologic sequelae including hypertension, hyperlipidemia, atherosclerosis (i.e., the metabolic syndrome, or syndrome X), and polycystic ovarian disease (1). Although many details of the mechanisms by which the enlarged adipose tissue mass that defines obesity causes systemic insulin resistance remain unknown, the past several years have witnessed an explosive increase in our understanding of what may now be referred to as the adipo-insulin axis. There are also grounds for considering the related possibility that insulin resistance and hyperinsulinemia, in addition to being caused by obesity, can contribute to the development of obesity. In this Perspective, we will review recent progress, highlight areas of controversy or uncertainty, and suggest approaches to clarifying the unresolved issues.
To investigate the associations of the apolipoprotein E phenotype (apoE) and disturbed glucose metabolism with cognitive function in a random population sample.
A cross-sectional study was conducted, in which 528 men aged 54 or 60 years were recruited randomly from a larger population-based sample of 1516 men. A subject was defined as having abnormal glucose tolerance (AGT), if he had a clinical diagnosis of diabetes, with either dietary or oral antidiabetic treatment or showed impaired glucose tolerance in an oral glucose tolerance test. The subjects were divided into three groups according to apolipoprotein E phenotypes: (a) E2/4, E3/4 or E4/4 (apoE E4); (b) E 3/3 (apoE E3); and (c) E2/2 or E2/3 (apoE E2). Memory function was examined using a word-list learning with Buschke's selective reminding method and test. Executive functions were assessed with the Trail Making Test A and B.
Those subjects with apoE E2 and abnormal glucose metabolism demonstrated the worst cognitive executive control compared to other groups. Simple cognitive speed did not differ between the groups.
The exploratory analyses revealed that subjects with apoE E2 allele and AGT had worse glycaemic control and cognitive executive control compared to other groups. Different apolipoprotein phenotypes together with impaired glucose tolerance may have different cumulative adverse effects on age-related cognitive performance. Some subgroups of subjects may be especially vulnerable to cognitive impairment.
Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension. Obesity, especially visceral adiposity, is negatively correlated with insulin sensitivity. The release of free fatty acids from adipocytes can block insulin-signaling pathways and lead to insulin resistance. In addition, recently identified adipocyte-specific chemical messengers, the adipocytokines, such as tumor necrosis factor-alpha, adiponectin, and resistin, appear to modulate the underlying insulin resistance. When insulin resistance is combined with beta-cell defects in glucose-stimulated insulin secretion, impaired glucose tolerance, hyperglycemia, or type 2 diabetes can result. The thiazolidinediones are potent peroxisome proliferator-activated receptor-gamma agonists and directly improve insulin resistance and glycemic control in patients with type 2 diabetes. Increasing evidence supports the early use of thiazolidinediones for preventing, delaying, or treating diabetes by improving insulin sensitivity and beta-cell insulin secretion.
Knockout mice are generated by using ES cells from 129 mouse strains and are frequently backcrossed with other strains, like C57BL/6. It is important to characterise the physiological and, in particular, the behavioural profile of each strain in order to correctly analyse the functional contribution of a single gene mutation on the 'cognitive' phenotype. The present study compared 129T2/Sv (129) and C57BL/6J (C57) mice in three different spatial learning protocols in the water maze, using a hidden platform. In the 'standard' reference memory protocol, 129 and C57 attained an equivalent level of performance as assessed by accuracy in reaching the platform (path length), despite a faster swim speed exhibited by C57 mice. In a stepwise learning task, C57 mice showed poorer performances over all stages of learning. However they performed better than 129 in a massed learning protocol which taxes short-term memory, and in which they exhibited lower levels of perseveration. The results emphasize the importance of using various tasks differing in cognitive demand, but using the same experimental environment and motivation, in order to 1) evaluate strain- or mutation-dependent learning abilities, and 2) dissociate the roles played by cognitive and non-cognitive factors in the behavioural requirements of the tasks.
Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein kinase B) has been recognized as being remarkably well conserved across a broad range of species and involved in a diverse array of cellular processes. Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiologically important target tissues. Refining our understanding of those pivotal molecular components that normally coordinate insulin action throughout the body is essential for a full understanding of insulin resistance in diabetes mellitus and ultimately the successful treatment of this disease.
We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.
Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia. In the present experiment, we measured cognitive function in 57 healthy male and female non-diabetic older participants who ranged in age from 55 to 84. Various biological measures were obtained including a glucose tolerance test during which glucose and insulin were measured. Participants were separated into better and poorer glucoregulatory groups on the basis of their blood glucose levels during the tolerance test. Participants were evaluated twice, once after drinking a saccharin solution and on another occasion after drinking a glucose solution (50 g). Older participants (72 years and over) with poorer glucoregulation had the worse performance in tests evaluating working memory, verbal declarative memory and executive functions. Glucose administration appeared to only attenuate the decrements observed in the saccharin condition in the older participants for some of the tests. These results suggest that cognitive functions may be impaired before glucoregulatory impairment reaches levels consistent with a type II diabetes diagnosis.
Nutrient selection emerges as a result of both genetic and environmental factors and may be further modified by stressors. The impact of this complex interrelationship on pathological outcomes is poorly understood. In the present investigation the stressor-reactive BALB/cByJ and the relatively stressor resilient C57BL/6ByJ mice were maintained on a macronutrient selection protocol or given free access to chow for 20 months. The C57BL/6ByJ mice exhibited a marked preference for fat over carbohydrates, whereas BALB/cByJ mice preferred carbohydrates over fat. Cognitive testing in a Morris water maze indicated that while BALB/cByJ mice were clearly more impaired in this task relative to their C57BL/6ByJ counterparts, there was no substantial effect of the diet at either 13 or 19 months of age. Furthermore, despite their stressor resiliency, at 19 months of age, C57BL/6ByJ mice who invariably consumed fat, exhibited greater plasma corticosterone responses to a 20-min period of restraint than chow fed animals. Indeed, the corticosterone rise was as pronounced as in the more reactive BALB/cByJ strain. Furthermore, the C57BL/6ByJ diet-fed mice showed features of insulin insensitivity and increased adiposity. These data suggest that the adverse effects of fat consumption need to be considered in the context of genetically determined vulnerability/resilience factors.
Temporary food restriction affects strain differences for behavioral phenotypes in the inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA). Since food restriction is a routine procedure to motivate learning, we evaluated its influence on differences for spatial and non-spatial discrimination between these strains of mice by using two non-associative tasks: the Spatial Novelty Test (SNT) and the Spontaneous Object Recognition Test (SORT). The results confirmed the poor performance of the DBA mice in SNT. Nonetheless, DBA mice were perfectly able to recognize the novel object in SORT. By contrast, C57 mice were good performers in SNT but failed to recognize a novel object in SORT. Finally, food restriction selectively improved C57 performance in SNT and DBA performance in SORT. These results support the view that a food restricting procedure enhances strain differences for discrimination of configurational information.
One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.
To examine the associations of fatty acid and fish intake with cognitive function.
Data are from a cross-sectional population-based study among 1,613 subjects ranging from 45 to 70 years old. From 1995 until 2000, an extensive cognitive battery was administered and compound scores were constructed for memory, psychomotor speed, cognitive flexibility (i.e., higher order information processing), and overall cognition. A self-administered food-frequency questionnaire was used to assess habitual food consumption. The risk of impaired cognitive function (lowest 10% of the compound score) according to the energy adjusted intake of fatty acids was assessed with logistic regression, adjusting for age, sex, education, smoking, alcohol consumption, and energy intake.
Marine omega-3 polyunsaturated fatty acids (PUFA) (eicosapentaenoic acid and docosahexaenoic acid) were inversely related to the risk of impaired overall cognitive function and speed (per SD increase: OR = 0.81, 95% CI 0.66 to 1.00 and OR = 0.72, 95% CI 0.57 to 0.90). Results for fatty fish consumption were similarly inverse. Higher dietary cholesterol intake was significantly associated with an increased risk of impaired memory and flexibility (per SD increase: OR = 1.27, 95% CI 1.02 to 1.57 and OR = 1.26, 95% CI 1.01 to 1.57). Per SD increase in saturated fat intake, the risk of impaired memory, speed, and flexibility was also increased, although not significantly.
Fatty fish and marine omega-3 PUFA consumption was associated with a reduced risk and intake of cholesterol and saturated fat with an increased risk of impaired cognitive function in this middle-aged population.
We have previously shown that the C57BL/6J (B6) mouse will develop obesity and diabetes if raised on a high-fat diet. Because high fat feeding is associated with hyperphagia, the present study was designed to separate the effects of fat from those of excess caloric consumption in this animal model. B6 mice were fed a low-fat diet (LF group) diet, high-fat diet (HF group) diet, or high-fat-restricted diet (HFR group), in which intake animals were pair-fed a high-fat diet to caloric level consumed by LF for 11 weeks. Within 3 weeks, HFR were significantly heavier than LF and, after 11 weeks, weight and glucose levels, but not insulin, were significantly increased in HFR when compared to LF. Body composition analysis showed the weight increase in HFR arose from an increase in percent fat consumed. We conclude that reducing the number of kilocalories consumed from a high-fat diet attenuates but does not prevent the development of type 2 diabetes and obesity in the B6 mouse.
A diet high in saturated fat (HF) decreases levels of brain-derived neurotrophic factor (BDNF), to the extent that compromises neuroplasticity and cognitive function, and aggravates the outcome of brain insult. By using the antioxidant power of vitamin E, we performed studies to determine the role of oxidative stress as a mediator for the effects of BDNF on synaptic plasticity and cognition caused by consumption of the HF diet. Male adult rats were maintained on a HF diet for 2 months with or without 500 IU/kg of vitamin E. Supplementation of the HF diet with vitamin E dramatically reduced oxidative damage, normalized levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), caused by the consumption of the HF diet. In addition, vitamin E supplementation preserved the process of activation of synapsin I and CREB, and reversed the HF-impaired cognitive function. It is known that BDNF facilitates the synapse by modulating synapsin I and CREB, which have been implicated in synaptic plasticity associated to learning and memory. These results show that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. Therefore, studies appear to reveal a mechanism by which events classically related to the maintenance of energy balance of the cell, such as oxidative stress, can interact with molecular events that modulate neuronal and behavioural plasticity.
The memory-improving action of glucose has now been studied for almost 20 years and the study of this phenomenon has led to a number of important developments in the understanding of memory, brain physiology and pathological consequences of impaired glucose tolerance. Glucose improvement of memory appears to involve two optimal doses in animals (100 mg/kg and 2 g/kg) that may correspond to two physiological mechanisms underlying glucose effects on memory. In humans, there have been few dose-response studies so the existence of more than one effective dose in humans is uncertain. Many tasks are facilitated by glucose in humans but tasks that are difficult to master or involve divided attention are improved more readily that easier tasks. There are a number of hypotheses about the physiological bases of the memory-improving action of glucose. Peripheral glucose injections could alleviate localized deficits in extracellular glucose in the hippocampus. These localized deficits may be due to changes in glucose transporters in that structure. Because certain neurotransmitters such as acetylcholine are directly dependent on the glucose supply for their synthesis, glucose is thought to facilitate neurotransmitter synthesis under certain circumstances. However, these hypotheses cannot account for the specificity of the dose-response effect of glucose. A number of peripheral mechanisms have been proposed, including the possibility that glucose-sensitive neurons in the brain or in the periphery may serve as glucose sensors and eventually produce neural changes that would facilitate memory processing. These latter results could be of importance because the mechanisms they suggest appear to be dose-dependent, a crucial characteristic to explain the dose-dependent effects of glucose. There may be an advantage to develop hypotheses that include both peripheral and central actions of glucose. There is evidence that impaired glucose regulation is associated with impaired cognition, particularly episodic memory. This impairment is minimal in young people but increases in older people (65 years and over) where it may compound other aging processes leading to reduced brain function. A small number of studies showed that glucose improvement of memory is associated with poor glucose regulation although this may not be the case for diabetic patients. Results of a few studies also suggest that drug treatments that improve glucose regulation also produce cognitive improvement in diabetic patients.
This study characterizes the high-fat diet-fed mouse as a model for impaired glucose tolerance (IGT) and type 2 diabetes. Female C57BL/6J mice were fed a high-fat diet (58% energy by fat) or a normal diet (11% fat). Body weight was higher in mice fed the high-fat diet already after the first week, due to higher dietary intake in combination with lower metabolic efficiency. Circulating glucose increased after 1 week on high-fat diet and remained elevated at a level of approximately 1 mmol/l throughout the 12-month study period. In contrast, circulating insulin increased progressively by time. Intravenous glucose challenge revealed a severely compromised insulin response in association with marked glucose intolerance already after 1 week. To illustrate the usefulness of this model for the development of new treatment, mice were fed an orally active inhibitor of dipeptidyl peptidase-IV (LAF237) in the drinking water (0.3 mg/ml) for 4 weeks. This normalized glucose tolerance, as judged by an oral glucose tolerance test, in association with augmented insulin secretion. We conclude that the high-fat diet-fed C57BL/6J mouse model is a robust model for IGT and early type 2 diabetes, which may be used for studies on pathophysiology and development of new treatment.
Adult male rats were fed a low or high fat diet and given psychosocial stress (crowded and unstable housing with daily predator exposure) for 3 weeks. Neither stress nor high fat diet, alone, produced dendritic atrophy; only the group given the combination of stress and high fat diet developed a reduction of the length and number of branch points of apical dendrites of CA3 neurons. These findings indicate that a synergy between high fat diet and stress caused a retraction of CA3 dendrites. The findings are consistent with work on peripheral (e.g., cardiovascular) systems demonstrating a synergy between stress and high fat diet, and are relevant toward understanding how diet and stress interact to adversely affect brain and memory processing.
There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. At present, several studies suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These findings were confirmed by studies in which high intakes of n-6 PUFA, n-3 PUFA, MUFA, and weekly fish consumption, providing large amount of n-3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the prevention and management of cognitive decline and dementia.
The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.
While considerable research has examined diminished insulin responses within peripheral tissues, comparatively little has been done to examine the effects of this metabolic disruption upon the CNS. The present study employed biochemical and electrophysiological assays of acutely prepared brain slices to determine whether neural insulin resistance is a component of the metabolic syndrome observed within the fructose-fed (FF) hamster. The tyrosine phosphorylation levels of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in response to insulin were significantly reduced within FF hamsters. Also, insulin-mediated phosphorylation of both residues necessary for activation of the serine-threonine kinase Akt/PKB, a key effector of insulin signaling, was markedly decreased. Elevated levels of the protein tyrosine phosphatase 1B, which dephosphorylates the IR and IRS-1, were also observed within the cerebral cortex and hippocampus of FF hamsters. Examination of whether a nutritionally induced compromise of neural insulin signaling altered synaptic function revealed a significant attenuation of insulin-induced long-term depression, but no effect upon either paired-pulse facilitation or electrically induced long-term potentiation. Collectively, our results demonstrate, for the first time, that nutritionally induced insulin resistance significantly affects the neural insulin signaling pathway, and suggest that brain insulin resistance may contribute to cognitive impairment.
This research summarises a research program that is concerned with the effects of high fat diets on cognitive function in rats. The diets selected accurately represent current upper limits of human fat consumption in western societies. Rats fed with diets high in saturated or unsaturated fat for 3 months, were severely impaired on a range of learning and memory tasks. Related studies showed that these effects were modulated by concentration of fat, environmental influences, and treatment with glucose. More work is needed to identify the neurobiological mechanisms underlying this impairment but saturated fatty acid intake, as well as insulin resistance and glucose intolerance may be important factors. In demonstrating a clear relationship between obesity and cognitive impairment, this research has important implications for aging. Older adults are particularly vulnerable to the adverse effects of dietary fat and the present results underscore the importance of evidence that seniors with marginal levels of nutrient intake often perform poorly on tests of cognitive function, and are at increased risk for various forms of dementia.