Mitigating the effects of high fat diet on the brain and behavior with berry supplementation

Amanda N. Carey * and Rachel L. Galli
Department of Psychology, Simmons College, Boston, MA, USA. E-mail: amanda.carey@simmons.edu; Tel: +617-521-2619

Received 16th June 2017 , Accepted 15th September 2017

First published on 18th September 2017


Research on the potential of berries to modulate the effects of high fat diets on the brain and behavior is a relatively small and growing field. This review provides an overview of current findings from animal studies assessing the impact of high fat diets supplemented with blueberries, blackberries, grapes and jaboticaba berries on cognitive performance and neuroprotection. High fat diets are demonstrated to increase brain markers of oxidative stress and inflammation and result in other neural alterations that can contribute to impairments in learning and memory. Berries are rich in bioactive polyphenols and show promise for mitigating the effects of high fat diet. Challenges to systematic research include variability in diet composition and regimens, limitations of predominantly male animal models, and other factors. Links between peripheral inflammation and CNS dysfunction have implications for the understanding of underlying mechanisms and directions for future research.


In colloquial language the word “berries” encompasses many types of small edible fruits and includes aggregate fruits like strawberries and raspberries.1 In botanical terms, berries are fruits with seeds and pulp produced by the ovary of a single flower, such as blueberries, cranberries, grapes, and bananas.2 Berries, broadly, have been demonstrated to provide a host of benefits for human health, including protection of the cardiovascular system from damage3 and anti-cancer benefits,4 possibly mediated by polyphenolic compounds in the berries.5 Additionally, berries have the potential to protect the central nervous system (CNS) from dysfunction. Berries are rich in a polyphenol called anthocyanins, which are red-purple plant pigments.6 The types and amounts of anthocyanins differ among berries, and can also depend on cultivation and harvest conditions. The components of berries, including anthocyanins, are known for their antioxidant properties and may be beneficial for maintaining peak neuronal functioning, given the high use of oxygen in the brain.7–11 The protection conferred by berries is likely also due in part to their other bioactive properties, most notably their ability to reduce inflammation12–15 and oxidative stress13,14 and increase neuroplasticity.14,16 Research has shown that berries can reverse, allay, or slow the progression of some of the behavioral dysfunction associated with aging7–10,13,14 or neurodegenerative disease,9,12,17 through a multitude of mechanisms.

The effects of obesity and high fat diet on the brain and behavior

Obesity is increasing worldwide; the WHO reports that in 2014, over 600 million adults were obese18 and in the US approximately 36% of adults qualify as obese.19 The standard American diet is characterized by excessive intake of saturated fats, refined sugars, and processed foods, as well as excessive energy intake and, combined with a sedentary lifestyle, it is a major contributor to the obesity epidemic.20,21 High energy, high fat diets (HFD) like the standard American diet can result in the development of obesity-related illnesses, such as type 2 diabetes, cardiovascular disease, and certain cancers.18,22 Most HFD research has focused on the cardiovascular system, insulin regulation and other peripheral effects. Less research has addressed how HFD may impact the brain and behavior.

There is accumulating evidence from animal studies to suggest that consuming a HFD may adversely affect the CNS. Evidence suggests that HFD consumption may result in behavioral deficits similar to those observed in aging animals, predominantly deficits in learning and memory.23–26 Animal studies using rodents indicate that the hippocampus may be particularly sensitive to the effects of high fat, high energy diets.24,26 The hippocampus is an area important for consolidation of declarative memories as well as spatial tasks, like navigating one's environment and understanding the relationship between objects or space.27 One study found that when three-month-old C57Bl/6 mice were fed a HFD (60% calories from fat) for 22 weeks prior to behavioral testing, the mice were impaired in object location memory, but not novel object recognition or fear conditioning, which are non-spatial tasks.24 The authors speculate that HFD consumption did not impair overall hippocampal memory formation, but that the impairment was specific to hippocampal-dependent spatial memory. In another study, 12-month-old C57Bl/6 mice were administered a HFD (60% calories from fat) or a western diet (WD, 41% calories from fat) for 16 and 21 weeks, respectively and were then evaluated using the Stone T-maze, which is a test of spatial memory.25 Performance of the mice fed HFD was impaired compared to mice fed a matched control diet, whereas the performance of WD-fed mice was not impaired. This was replicated in aged mice; retention was impaired in the Stone T-maze in 20-month-old C57Bl/6 mice fed HFD for 16 weeks, but not those fed the lower fat WD.26

A possible mechanism by which HFD may affect cognitive abilities is through increasing oxidative stress26,28,29 and inflammation.28–30 In fact, obesity is associated with chronic low-grade inflammation throughout the body30 and cognitive dysfunction.31 In the above discussed studies of mice fed HFD and WD, there was an increase in oxidative stress markers in the hippocampus with the HFD, but not with the WD.26 HFD also reduced a mediator of the body's endogenous antioxidant response, nuclear factor-E2-related factor 2 (Nrf2), but again the WD did not have an effect. HFD consumption significantly increased expression of the inflammatory cytokines tumor necrosis factor-alpha (TNFα) and interleukin (IL)-6 in the cortex and increased reactive astrocytosis and microgliosis.25 More recently, Almeida-Suhett et al.32 demonstrated that HFD-fed mice had impaired working memory in the Y-maze, and this cognitive impairment was correlated with IL-1β expression in the hippocampus and amygdala. There was also more staining of microglia and astrocytes in the hippocampus of the HFD-fed mice compared to mice fed a control diet, suggesting that increases in glial cell number or activity may be mediating the changes in cytokine expression and inflammation.32

HFD may also mediate learning and memory impairment by reducing neuroplasticity. HFD has been shown to reduce the expression of the brain-derived neurotrophic factor (BDNF),25,33 which is important for brain plasticity because of its role in the survival, maintenance, and growth of neurons34 and memory.35 Notably, inflammation and oxidative stress may play a role in modulating BDNF.36 HFDs have also been shown to reduce neurogenesis, possibly by decreasing BDNF and increasing lipid peroxidation.33

Importantly, consumption of berries has been shown to mitigate the oxidative stress and brain inflammation and subsequent cognitive dysfunction associated with aging13,14,37 and neurodegenerative disease.12,17,38 Berries have also been shown to increase neurogenesis39,40 and the expression of BDNF.16,40–42 Thus, berries have the potential to mitigate the effects of HFD on the brain and behavior by reducing oxidative stress and inflammation and increasing neuroplasticity.

This review will focus on the research investigating the ability of berries to reduce the brain and behavioral alterations induced by eating a HFD. This review will also discuss some of the limitations and complications associated with this research and suggest possible directions for further studies. As much of this research is in its infancy, the main focus will be in vivo animal research. However, a discussion will be included about how the results of clinical research examining the effects of berries on peripheral inflammation may have implications for brain and behavior research.

The ability of berries to mediate the effects of HFD on the brain and behavior

Blueberries

Animal research has shown that diets supplemented with blueberry can allay behavioral deficits associated with consumption of a HFD. In a previous study, nine month old C57Bl/6 mice were fed a HFD (60% calories from fat) or a standard control diet (10% calories from fat) with and without 4% blueberry (freeze-dried whole berry).43 Mice were assessed with a novel object recognition memory test after 8, 12, and 16 weeks on the diets. The novel object recognition test measures the ability to remember an object by observing reaction to the introduction of a novel object compared to an object viewed in previous acquisition trials. Animals with unimpaired memory will spend more time interacting with the novel object in the testing trial. Recognition memory was impaired by the HFD, but blueberry-supplementation reversed recognition memory deficits in a time-dependent manner.44 The performance improved over the three test sessions, and after 16 weeks on the HFD, blueberry-supplemented animals performed similarly to mice fed the standard, control diet.43 After 18 weeks on the diets, mice were tested in the Morris water maze, a paradigm that requires mice to use spatial memory and distal cues in the testing room to find a hidden platform in a circular pool of water. Probe trials were conducted as the last trial of the day on the second and third days of testing. During this trial the platform was removed and the number of times the animal passed through the platform location was assessed. Probe trial performance in the Morris water maze was impaired in animals consuming HFD, while animals on the HFD with blueberry were not different from those fed control diet.43 Notably, blueberry supplementation did not prevent the weight gain associated with consuming a HFD. After 20 weeks on the diets, brain tissue was harvested and assessed and it was found that mice fed the HFD diet with blueberry had enhanced BDNF and neurogenesis in the hippocampus compared to mice fed the HFD without blueberry.44 The protection against HFD-induced deficits is congruent with previous findings demonstrating blueberry supplementation mitigates a number of changes in the brain and behavior associated with normal aging8–10,14 and age-related disorders.9,10,16

Blackberries

There is accumulating evidence from empirical animal studies that blackberries may also be beneficial in combating the effects of HFD on the brain. Two recent publications reported beneficial effects of an anthocyanin rich blackberry extract on brain outcomes in rats fed a HFD.45,46 Two month old Wistar rats were fed a standard maintenance diet or a HFD (45% calories from fat) with or without blackberry supplementation.45 An ethanol extract of whole blackberries was concentrated and purified and the amount added to the diet was adjusted weekly for a daily anthocyanin dose of 25 mg per kg body weight. Supplementation with the blackberry extract did not mitigate weight gain associated with consumption of the HFD. After 17 weeks on the diets, when the rats were approximately six months old, neuroinflammation was assessed in cortex and hippocampus. As expected, the HFD altered the expression of multiple proteins. Of note, up-regulation of several markers of inflammation was blocked by the blackberry supplementation, including levels of the receptor for advanced glycation end products (RAGE). Increased levels of RAGE are indicative of oxidative stress,47,48 associated with abnormal glucose metabolism,47,49 another potent source of free radicals and inflammation, and correlated with increased production of beta amyloid.50,51 Although the blackberry extract did not influence cytokine levels in the hippocampus, cortical inhibition of the HFD-induced rise in RAGE is evidence of neuroprotective activity.

A follow up study measured levels of the neurotransmitter dopamine in the prefrontal cortex and striatum of rats administered the same 17-week regimen of standard or HFD diet with or without the blackberry extract high in anthocyanins.46 The authors estimated that the amount of blackberry anthocyanins administered was comparable to an adult human eating 100 g of blackberries a day. The results demonstrated a significant interaction between diet and berry supplementation in the striatal samples, but not in prefrontal cortex. The HFD significantly increased the amount of dopamine, quantified by high performance liquid chromatography, while supplementation of the HFD with blackberry resulted in dopamine levels at normal control diet levels. This suggests that consuming blackberries has the potential to mediate brain changes associated with chronic consumption of a diet high in fat.

Grapes

Grapes are berries that are relatively high in flavonoids and resveratrol.52 Demonstrated beneficial effects of grape juice include moderating age-related cognitive decline in humans53 and animals.54 Treatment with juice, as well as other grape preparations, has reduced markers of oxidative stress in plasma, brain tissue, and in cells grown in vitro, supporting the idea that the antioxidant effects of grapes likely contribute to improved brain and behavior function.55–57 Evidence of antioxidant protection in the CNS has led to grapes being evaluated in animal models investigating the effect of HFD on the brain.

In a 2012 study by Charradi et al., a grape seed and grape skin extract was prepared from wine pomace and assessed for potential neuroprotective effects against HFD-induced oxidative stress.58 Either the extract or vehicle alone was administered by daily i.p. injections to two-month-old Wistar rats fed either a standard diet or a HFD for 6 weeks. The HFD was 28% sheep fat, similar to lard, added to a standard rodent chow containing 3% fat. Animals on the HFD plus vehicle injections gained significantly more weight than the other three groups, including the HFD plus grape extract subjects. The changes in brain levels of oxidative stress and lipid peroxidation were assessed by multiple measures. Charradi and colleagues reported that all of the HFD-induced effects detected in the brain were blocked by concomitant treatment with the grape seed and skin extract.58 Whole brain homogenates were processed and spectrophotometric assays illustrated that the changes in lipid peroxidation (malondialdehyde), protein carbonylation, and sulfhydryl radicals were absent in samples from the grape treatment HFD group when compared to the HFD plus vehicle. The grape extract also protected against a decrease in the antioxidant activity of glutathione peroxidase (GPx) and the magnesium (Mn) isoform of superoxide dismutase (SOD). In light of Mn-SOD finding, brain levels of Mn and other metals were examined. In this study, significantly lower amounts of Mn were detected in the brains of HFD plus vehicle animals, while HFD supplementation with grape extract was associated with normal Mn levels. Based on these data, the authors postulated that a significant drop in Mn levels due to long term consumption of a HFD might influence a range of CNS functions.

Another study examined the effects of conventional purple grape juice as well as organic purple grape juice in young Wistar rats fed a HFD.59 The organic grape juice was found to be approximately 40% higher in polyphenols and four fold higher in resveratrol than the conventional juice. The lipid/carbohydrate/protein composition of the HFD employed was 59%/20%/21% while the standard diet was 12%/63%/25%; neither diet included vitamins or minerals and the source of the lipids was saturated fatty acids. Subjects were assigned to one of the four nutritional treatments: the HFD plus either conventional grape juice, or organic grape juice, or water, and a control group that received the standard diet plus water. Under all conditions the subjects had free access to food and drink (juice or water). The conventional and organic grape juice groups consumed fewer total calories than the control group and the HFD diet group drinking water. At the end of twelve weeks the HFD plus water group gained significantly more weight than the other three groups.

In this study, the cerebral cortex, hippocampus, and cerebellum, were tested for standard markers of oxidative stress and lipid peroxidation following the three months of HFD with or without purple grape juice consumption.59 The impact of the HFD varied by brain region and was ameliorated in most cases by grape juice. Interestingly, the organic and conventional juices at times varied in the degree of protection provided, with the organic juice proving more potent. For example, increased measures of oxidative damage were found in the cortex and the cerebellum but not the hippocampus of HFD-fed animals. The results demonstrated that only the organic grape juice reduced lipid peroxidation in cerebral cortex and cerebellum, while both organic and conventional grape juices reduced protein oxidation in these brain regions. Additionally, enzymatic antioxidant defense (i.e., SOD activity) was reduced by HFD in all three brain regions; while conventional and organic grape juice enhanced SOD activity in cerebral cortex and hippocampus only. This illustration of brain region specific changes and response to dietary supplementation begins to shed light on the complexity of nutrient action within the CNS. The pattern of the results showing organic juice to be generally more effective is in line with the higher levels of polyphenols and resveratrol found in juice from organic grapes. Lacking treatments used in conventional farming, organic fruits may increase production of bioactive compounds like polyphenols to protect themselves against environmental challenges.

Two publications from the Lin laboratory explored the interaction of dietary supplementation with grape powder, long term consumption of a diet high in fat and high in fructose (HFHFD), and age-related changes. One article reported on behavioral measures of learning and memory,60 the other evaluated hippocampal and cortical brain samples for markers of oxidative stress, antioxidant activity, and neuroplasticity.61 The following procedures (groups, diets, time course) were employed in both studies, prior to assessment of either behavioral or neuronal variables.60,61 The HFHFD contained 20% (w/w) fat from soybean oil and 61.5% (w/w) fructose. The lipid/protein/carbohydrate energy ratios of the control diet (AIN-93 M) and HFHFD were 9/15/76 and 18/12/50, respectively. Wistar rats were fed the HFHFD (n = 50) or control (n = 10) diet beginning at 2 months of age. After 50 weeks, the control group and ten HFHFD subjects were removed from the experiment following cognitive testing and/or sample collection. The remaining rats (n = 40) continued on the HFHFD. At week 58 the intervention phase began, with the goal of evaluating the extent to which grape or drug treatments might mitigate the effects of the HFHFD. Grape powder was produced from lyophilized whole fruit and incorporated into the food pellets at low and high concentrations. Groups (n = 10) continued on the HFHFD, supplemented with either 3% grape powder, 6% grape powder or 0.05% of the diabetes medication metformin HCl. The control group continued on the HFHFD without supplementation. The intervention phase lasted for 12 weeks and concluded with behavior testing and brain sample collection. At this time the animals were 19.5 months old and had been on the HFHFD for almost a year and a half.

Learning and memory were measured with the Morris water maze.60 In comparison with the control group, the HFHFD rats performed significantly worse on the probe trial test of retention. Following the 12 week intervention phase, memory retention was significantly improved by supplementation with grape in low or high concentration or with Metformin compared to HFHFD alone. Long term consumption of the HFHFD had a negative impact on brain outcomes61 that were in alignment with the behavioral findings,60 demonstrated by changes in a wide range of markers in cortex and hippocampal samples assayed by western blot.61 HFHFD increased levels of RAGE in the hippocampus and cortex; this change was ameliorated by supplementation with 3% and 6% grape powder and 0.05% metformin.61 Furthermore, HFHFD reduced Nrf2 in cortex and hippocampus, indicating a reduction in endogenous antioxidant capacity. The decrease was mitigated by metformin and in a dose-dependent manner by the grape powders.61 BDNF was also decreased in rats fed HFHFD, but the grape powders dose-dependently reversed this in the hippocampus, while only the 6% grape powder enhanced BDNF in cortex. Notably, metformin did not protect the brain from HFHFD-associated reductions in BDNF. Overall, the higher concentration of 6% grape powder proved most efficacious. On several measures, including BDNF, the HFHFD plus 6% grape powder resulted in better outcomes than what was found in the 50 week control diet brains.60,61 Supplementation with grapes appeared to have the potential to not only moderate or reverse alterations induced by the fructose- and fat-rich diet, but also to counteract changes related to normal aging.

Jaboticaba berry

Jaboticaba (Myrciaria cauliflora) is a Brazilian tree fruit that when ripe has a thick dark purple skin rich in polyphenols.62,63 In a recent study, jaboticaba berry skins, more commonly called peels, were demonstrated to protect against HFD-induced changes to the brain and behavior.64 The peels of the fruit were processed by heat drying and homogenization into a powder that was added at 4% w/w to both control and HFD. Here, a standard AIN93-M maintenance diet with 4% soybean oil was used for control conditions and the HFD included the addition of 31% w/w lard. Jaboticaba peel powder was determined to be high in fiber, carotenoids, flavonoids and polyphenols, especially cyanidin-3-0-glucoside and ellagic acid.62,64 Two month old Swiss mice were given free access to one of four diets: control with or without 4% jaboticaba powder and HFD with or without the jaboticaba supplementation. During week eight on the diets, the animals were tested in the Morris water maze. When the study ended at ten weeks, berry supplementation had prevented HFD associated weight gain.

Jaboticaba supplementation protected against HFD-induced impairments in both learning and memory.64 Mice fed the HFD without supplementation were significantly slower in finding the platform on acquisition days four and five. They also performed worse on a probe trial measure of retention on day six. In contrast, HFD plus jaboticaba-fed mice spent more time in the target quadrant and crossed the platform location more times during the probe trial and displayed better learning on day four, similar to the control diet group. Adding jaboticaba berry peel to the control diet had no effects on the brain or behavior, while in combination with HFD it protected against most HFD-induced deficits in learning and memory.

Congruent with whole brain findings reported with other berries, HFD associated decreases in SOD activity and increases in lipid peroxidation levels were absent in frontal cortex samples from jaboticaba-supplemented HFD brains.64 Further evidence of neuroprotective effects was seen in lower levels of inflammatory markers TNFα and interferon gamma (INFγ) in the hippocampal regions of these subjects. An increase in Tau phosphorylation, characteristic of Alzheimer's disease, was also seen with the HFD. This change along with increased phosphorylation of the insulin signaling proteins IRS and GSK3-β was also prevented by the dietary supplementation. The finding that jaboticaba berry peel had a beneficial effect on markers of neurodegeneration and dysfunction in insulin signaling and minimized HFD-induced weight gain led the authors to consider its potential relevance targeting the obesity–insulin insensitivity–Alzheimer's disease connection.

The link between peripheral inflammation and central nervous system dysfunction

Consumption of a high-fat high-energy diet contributes to obesity and is associated with peripheral inflammation.29,65,66 In humans and animals, chronic peripheral inflammation and obesity have been linked to cognitive impairment, including deficits in learning and memory,67,68 and disrupted adult hippocampal neurogenesis.69 The interaction of peripheral inflammation and the brain has not been fully elucidated, in part because the brain was once thought to be immune privileged and isolated from the peripheral immune system because of the blood brain barrier and lack of lymphatic system. However, there is increasing evidence that communication between the CNS and periphery is more evident and dynamic than previously thought. There is evidence that peripheral cytokines may enter the brain through areas where blood brain barrier protection is limited or non-existent, such as regions involved in endocrine regulation70,71 or locations near the ventricles.71,72 It has also been postulated that circulating macrophages can communicate with microglia, the brain's resident immune cells, or that certain cytokines may enter the brain through active transport.73 If reductions in peripheral inflammation can have a significant impact on the brain and behavior, then this suggests that the degree to which berry polyphenols can permeate the blood brain barrier may be a less important factor for their beneficial effect on the CNS than previously thought.

Non-human animal studies

Animal models provide evidence that regular berry consumption may be a promising strategy to mitigate metabolic abnormalities and complications in those that are obese or overweight with metabolic syndrome.74,75 Given that peripheral inflammation may result in CNS inflammation and possible cognitive changes, it is also important to examine studies that evaluate the effects of berries on HFD-induced changes in peripheral inflammation. It has previously been demonstrated that expression of adipose tissue inflammatory mediator genes such as TNFα and IL-10 was upregulated in mice fed HFD for 8 weeks, but attenuated in mice that were supplemented with 4% whole blueberry powder.76 In a recent study, mice were fed a HFD with or without oral gavage of grape seed proanthocyanidin extract (300 mg per kg body weight per day) for 7 weeks.77 Treatment with the grape seed proanthocyanidin extract significantly decreased plasma levels of inflammatory cytokines such as TNFα and IL-6.

Clinical research

Despite the difficulty in conducting clinical studies, the importance of clinical research cannot be overstated, as animal models cannot fully recapitulate the effects that a dietary intervention may have in humans. Furthermore, the connection between peripheral and CNS inflammation in humans is complex and yet to be well characterized. Epidemiological studies have linked peripheral inflammation or chronic peripheral inflammatory diseases with neurodegenerative diseases like Alzheimer's and Parkinson's disease, although a causal link has not been thoroughly established.73 Importantly, studies have shown that berry consumption has the ability to reduce peripheral inflammation. Sardo et al. completed a study in which overweight and obese males were fed 45 g per day of freeze-dried black raspberries for 4 days and then were given a high fat high calorie breakfast on day six.78 This was a cross-over design; participants consumed the high fat high energy meal after consuming black raspberry and also without black raspberry pre-treatment (with a 2-day washout period in between). Postprandial concentration of serum IL-6 was reduced in participants when they consumed black raspberry prior to the challenge meal. In a similar study, postprandial responses to a high fat high carbohydrate meal were assessed in overweight and obese male and female participants after 6 weeks of daily strawberry beverage intake.79 The beverage contained freeze-dried strawberry powder equivalent to approximately 100 g of fresh strawberries. IL-1β was reduced in the plasma of participants consuming the strawberry beverage compared to those consuming a placebo.

Considerations for systematic research and future directions

Designing experiments using HFD

Designing HFD experiments requires choices of nutritional composition of the control and HFD diets, the amount and source of fat, the length of time subjects are on the diets, and the age and species of the subjects. Modeling an unhealthy human diet can go beyond increasing fat content to incorporate high levels of sugar as well. Sugar and fat may have differential effects on weight80,81 and glucose intolerance82 in mice, but effects on the CNS are less clear.80 It has been demonstrated that HFD diets that also are high in refined sugars impair spatial memory and reduce neuroplasticity in the hippocampus of rats82 in ways similar to a HFD.23,24,33 A recent study demonstrated that diets high in sugar or high in both fat and sugar had comparable effects on rat hippocampal-dependent memory and brain inflammation.83 Resveratrol, a compound found in grapes and other fruits, has been shown to mitigate the effects of a high fat/high sugar diet on brain inflammation and oxidative stress in non-human primates.84 However, the effects of a HFD versus high sugar diet on the central nervous system remain to be fully characterized.

Research making more direct comparisons between the effects of different types of fatty acids in combination with berry supplementation is important to consider. Many of the studies reviewed here utilized diets that are high in energy (calories), obesogenic, and high in saturated fatty acids. It should be noted that not all fats are created equal and there is no regularity in the source of fat incorporated into HFDs; among the most commonly employed are pork lard and soybean oil. Studies have found differential effects of fats on the brain. For example, lard-based diets high in saturated fatty acids have been shown to impair learning and memory in rats, while rats fed a soybean oil-supplemented diet high in polyunsaturated fatty acids were less impaired.85 Polyunsaturated fatty acids have also been shown to protect against the development of insulin resistance86 and cardiovascular disease,87 and are associated with decreased incidence of type 2 diabetes88 and risk for dementia,89 while saturated fatty acids may increase the risk of developing these health complications.86–89 In a previous study, rats fed HFDs with 42% of the calories from lard or olive oil showed more pronounced obesity and insulin resistance than rats fed HFDs with 42% of the calories from coconut or fish oil.90 This study illustrates that dietary fatty acid profiles can differ in effects on metabolic parameters. Although beyond the scope of this review, it is important to highlight that polyunsaturated omega-3 fatty acids may actually reduce inflammation and cognitive dysfunction associated with aging, neurodegenerative disease, and obesity/overweight.91–93 It is feasible that future research may reveal a possible synergism between berries and omega-3 fatty acids in the protection against cognitive decline.

Using humans or non-human animals in research

In animal models, species and strain have the potential to influence outcomes in nutrition and behavior studies. Two popular rat models to study diet-induced obesity are the Wistar and Sprague Dawley rat. Research has shown that both rat strains shown increases in weight, body fat mass, and markers of metabolic dysfunction, such as decreased oral glucose tolerance, when fed a HFD but that the majority of these effects are more pronounced or detected earlier in Wistar rats.94 Furthermore, it is not always clear how well these models recapitulate the effects of diet-induced obesity in humans. The C57Bl/6 mouse is also a commonly used model of diet-induced obesity. When allowed free access to HFD, C57Bl/6 mice develop hyperinsulinemia, hyperglycemia, and hypertension, in ways that parallel many of the disease patterns that occur in humans who consume a HFD.95,96

Admittedly, there will always be limitations in the application of rodent research to humans. Thus, the importance of clinical research cannot be overstated; however clinical research also has many challenges. Foremost among the many factors that make research in humans challenging, such as cost, time, recruiting, compliance and attrition, there are also ethical issues to designing a human study modeling diet-induced obesity or the effects of long-term consumption of a HFD. Typically, research involves short-term HFD consumption or a single challenge meal or provides only correlational data using a subset of overweight and obese participants, which may lack the control of other influential variables, such as activity level. Animal models are a way to control for these methodological and ethical issues, and allow researchers to further explore mechanisms by which HFD may affect the brain and behavior, as well as test berries as potential interventions.

The effects of berries on the brain and behavior in humans and rodents fed HFD may also be influenced by sex. Notably, research shows that the impact obesity has on health and cognitive dysfunction may be a sex-dependent effect, as the impact has been shown to be greater in men.68,97 Furthermore, berries have been shown to have differential effects on cardiovascular disease factors98 and the metabolism and distribution of flavanols in the body99 between males and females. These sex-differences may prove to be a major issue to generalizing findings. Research, particularly rodent research, often uses only male animals, as is the case with all of the animal studies reviewed here. It is becoming increasingly important to include both female and male subjects in order to delineate any sex difference there may be in response to HFD with and without berry supplementation.

Conclusion

Much remains to be known about the ability of berries to mitigate the insults inflicted on the brain by diets high in fat; however the results from the limited number of animal studies currently in the literature are promising. Given the rapid rise in obesity and its related chronic conditions that can contribute to inflammation, oxidative stress, CNS dysfunction and associated deficits in behavior, there is a grave need for interventions with the potential to reverse impairments in neuronal and behavioral function. Although methodological challenges for generalizing results across HFD/berry supplementation studies are many, similar obstacles have been overcome in other fields of research and have contributed to advances in clinical interventions. Even though the amount of berries being consumed has been increasing over the past decade, berries make up a relatively small portion of the American diet, compared to processed foods or fruits like apples and oranges.100 Rich in polyphenols and other bioactive compounds, effective doses of berries may present an achievable goal among potential dietary changes targeting the consequences of diets high in fat.

Conflicts of interest

There are no conflicts of interest to declare.

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