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The prevalence of obesity in men and women is
increasing in developed and developing countries around the world. Human and
animal investigations indicate that obesity adversely impacts people health,
predisposing them to chronic diseases such as dyslipidemia, hypertension, type
2 diabetes mellitus, cognitive dysfunction, brain ischemia, Alzheimer’s disease
and so on. High fat diet induces oxidative stress which may be involved in
civilization neurodegenerative diseases such as mild cognitive impairment and
Alzheimer’s disease. In this study, we have evaluated influence of quercetin on
obesity-induced cognitive decline. Thus, in the obesity-induced cognitive
decline, an appropriate dose of quercetin can reduce oxidative stress resulting
in an enhancement of hippocampus dependent cognition. But under a balanced
condition, quercetin may force pro-oxidant effects and worsen cognition.
Key words: Obesity, Cognitive
decline, Neurodegeneration, Brain ischemia, Alzheimer’s disease, Quercetin,
Oxidative stress.
INTRODUCTION
Obesity is described such as abnormal and/or unrestrained accumulation
of body fat and is considered present when a person's weight exceeds desirable
weight by 20%. Worldwide obesity levels have increased unprecedentedly over the
past couple of decades [1]. Circa one-third of adults meet criteria for obesity
(BMI >30), approximately 17% of women and 12% of men have severe obesity
(BMI>35) in the United States [2]. Studies have shown that obesity is a risk
factor for poor neurocognitive outcomes, including mild cognitive impairment, Alzheimer’s
disease and other forms of dementia, cardiovascular disease, metabolic
syndrome, cancer and so on [3-8] and may increase multi-morbidity [9]. Current
investigations have noted that severe obesity is also associated with increased
risk for cognitive decline, and this risk appears to be elevated with age
[10-12]. The awareness of the modern world obesity as a major health problem
and an uncontrolled worldwide epidemic has to be increased in the society
[6,13,14]. The epidemic of obesity is a global health problem that is expected
to rise considerably in low- and middle-income countries, too. Their
populations, shift from a traditional diet to more western pattern of diet and
are engaging in sedentary activities [15]. As a result, the prevalence of people
obesity in these countries is significant with substantial variation in levels
and trends in different countries. Over the past 20 years, obesity rate
increased from 15% in 1980 to 32% in 2004 among adults in the United States
[16]. More than 60 million people (30%) of the United States adults aged ≥20
years are obese; the prevalence among members of minority groups is even higher
[16]. In New Zealand, circa 29% of adults now are classified as obese [17].
Obesity is also increasingly prevalent among children and adolescents.
Approximately, 38% and 17% of children and adolescents, respectively, in the
United States are obese [18]. The prevalence of obesity is rising alarmingly
among children and adolescents in the China, with an estimated 120 million now
in the obese range [19]. According to the WHO global estimates in 2013 were
nearly 700 million adults obese across the world [1,18]. Obesity and overweight
are widespread in women of procreative age [20-25]. In Ghana, the predominance
is 37.1% [20], in the United States 35.5% [23], in the United Kingdom 33% [24],
in Mexico 32.4% [21], in Brazil 16.1% [22] and in China 16% [25]. Maternal
obesity can result in negative metabolic diseases for both the mother [26,27]
and the offspring [26,28-30]. Obesity rise exponentially worldwide to almost
epidemic ratio [6,13,14]. The World Health Organization has declared obesity as
one of the top ten adverse health risk factors in the world [31]. Today
worldwide, 1.5 billion population is overweight or obese [14].The recent rise
in obesity rates is associated with the interaction between changes in dietary
habits such as augmented consumption of foods that are either industrially
processed or high in energy, lower physical activity and genes [31-33]. The
evaluated complete digits of overweight and obese adults in 2005 were 937
million and 396 million, respectively [34]. If latest trends continue without
any reduction in intensity and/or strength, the amount of individuals were
estimated to complete 2.16 billion overweight and 1.12 billion obese persons,
by 2030 [34,35]. This review will focus on obesity-induced cognitive decline and
how supplementation of quercetin can improve neurocognitive outcomes.
Obesity-Related Diseases
It is well known that higher rates of obesity have been linked to
higher rates of obesity-related diseases, such as some cancers, heart disease,
hypertension, type 2 diabetes, respiratory diseases, stroke and
neurodegenerative disorders like mild cognitive impairment,
Alzheimer’s disease and different forms of cognitive decline
[16,36,37]. This presents an increasing economic and social burden to
individuals, families and the healthcare system [1].
Today obesity and obesity-induced disorders are the main focus of
healthcare providers and healthcare policy due to its sustained increase in
prevalence over the last decade [38]. A consistent body of evidence now demonstrates
that being overweight or obese in childhood and adolescence has health
consequences and leads to increased morbidity and premature mortality in
adulthood [39]. Relative to normal weight, both obesity grades 2 and 3 were
associated with significantly higher all-cause mortality [40]. As obesity and
dementia rates reach epidemic proportions, an even greater interest in the
effects of nutrition on the brain have become evident. The basis for the
inter-relationships between chronic obesity and cognitive decline and others
diseases lay at a basic intracellular level that is oxidative stress [38].
Augmented oxidative stress, which is attributed to an excessive production of
reactive oxygen species and/or impaired antioxidant defense machinery in body,
seems responsible for the abnormal gain of weight in obese subjects [38].
Preventing obesity and obesity-induced disorders are the optimal long-term
population strategy [37] and must be a government’s priority. There are many
approaches which could be taken to facilitate this, however it is important not
to forget those who are currently obese. The costs of obesity and its
consequences are staggering for any society, crippling for countries in
development [1]. Many different therapeutic approaches in obesity and
obesity-induced cognitive decline have been investigated including exercise,
diet [37], behavioral therapy, and medication. None have been found to be
effective enough as sole tool in this health problem. In order to improve the
quality of the health care and to minimize the cost, it is important to
investigate and standardize prevention and/or treatment and to adapt them to
social and cultural aspects. Today, nutrition research has moved on from the
traditional concepts of avoiding nutrient deficiencies and basic nutritional
adequacy to the new concept of positive and/or optimal nutrition [37]. Many
traditional food products including vegetables, fruits, flaxseed, barley, oat,
whole grains, and milk have been found to contain component with potential health
benefits. Nowadays, functional foods can be used in the prevention and
amelioration of several chronic diseases, such as the obesity-related disorders
[37,41].
Obesity-Related Cognitive Decline and
Treatment by Quercetin
The paper
by Xia et al. [8] deals with the nature of the problem population obesity along
with their own proposal in the treatment of obesity-induced disorders dangerous
to health such as cognitive decline. Above study addresses the new therapeutic
options in the treatment of obesity-induced cognitive decline with special
emphasis on emerging knowledge of its genetics [8]. This timely study is a
2-side discussion paper which serves to define the dangerous relationship
between obesity, cognitive decline, genes [37] and quercetin. The authors
investigate the diverse effects of quercetin under different diets. Quercetin
(3,3ʹ,4ʹ,5,7-pentahydroxyflavone) an important flavonoid found in apples,
citrus fruits, red onion, berries, tea, and red wine is one of the most common
flavonoids in the human diet. Because quercetin is plentiful in plant-based
products in the diet, it is important to determine whether quercetin can reduce
human health challenges such as obesity and obesity-induced cognitive decline.
Hence, they have characterized the effects of quercetin in an appropriate
animal model of diet-induced obesity and associated cognitive decline. Their
rodent model mimics most of the problems associated with human obesity.
Quercetin is a potent antioxidant and exhibits some vital medicinal properties.
In fact, growing body of evidence shows that flavonoids regulate the activities
of metabolizing enzymes, modulate gene expression, nuclear receptors, and
subcellular signaling pathways, and repair injured DNA by oxidative stress
[42-45]. Free radicals, which can damage cell membranes and DNA through a
process known as oxidative stress, are blamed for many of the diseases
associated with obesity.
Xia’s and colleagues [8] discus various mechanisms by which a high fat
diet can alter the brain and cognition [37]. The balance of evidence from their
paper indicates that high fat dietary pattern predisposes to obesity and
damages the brain and cognition. To the best of our knowledge, this is the
first research to document the relationship between a high fat diet, oxidative
stress, gene dysregulation and cognition changes in a more detailed way and one
of the first to hold the view that quercetin can enhance memory. Their report
was to determine the protective and detrimental effects of quercetin on
hippocampus dependent learning and memory in mice fed with either normal or
high-fat diets. The authors demonstrated that the supplement of quercetin can
improve cognition in only high-fat diet group, but not in the normal diet
group. The authors give the reason of their findings that quercetin may act as
pro-oxidant agent in normal situation, but quercetin acts as anti-oxidant agent
in high oxidative stress condition. The authors proposed that the beneficial
effect of quercetin was on the cellular effects by the interactions with
specific proteins involved in intracellular signaling such as improving of
Pi3k/Akt signaling followed the augmentation of BDNF expression [46]. One of
the major defense systems against oxidative stress-related injury is the Nrf2
system. Nrf2 is a transcription factor present in inactive forms in the cell.
Once activated, Nrf2 translocates to the nucleus and activates the antioxidant
response machinery. This, in turn, gives rise to enzymes and proteins, such as
HO-1, which reduce the cellular oxidative stress. This suggests that the
activation of Nrf2 system by quercetin can protect hippocampus dependent
function. Their data show that the genes such as Creb, Bdnf, Pi3k, Camk II,
Nrf2 and Akt, originally identified as a pathogen sensor and a proposed
regulator of the cognitive function response against oxidative stress, are down
regulated in the hippocampus of obese individuals. One most important point in
quercetin action is probably related to the integration of signals from
different molecules with similar biological functions. It is very likely that
each of these factors plays a role in diet-induced obesity and/or
obesity-induced cognitive decline.
However, long-term effects of obesity on the brain need to be further
examined. The aspect of the diverse effects of quercetin, depending on food
categories, may look controversial at a fist glance [46]. The appearance of
controversy may arise in part because studies of different doses of quercetin
(low and high) in different diets (normal and high fat) are completely new.
Quercetin high dose intervention results in large effects on down
regulated genes involved in learning and memory. Xia and colleagues [8]
presented strong evidences to support beneficial effects of quercetin on
obesity-induced cognitive decline. However, given the unexplained heterogeneity
these findings must be interpreted cautiously. Strengths of their study include
the assessment of markers of oxidative stress in serum and hippocampus at
baseline and after the intervention, measurement food intake, blood glucose,
serum lipids, body weight, learning and memory and gene dysfunction. Currently
some research in experimental models of Alzheimer's disease [47,48], brain
ischemia [49] and aged animals [50] support the beneficial effect of quercetin
on cognitive decline.
Conclusions
The paucity of literature on treatment of obesity-induce cognitive
decline in humans points out the need for much additional research on obesity
and obesity linked diseases [8,37].
However, further studies considering gene-gene and
gene-environment-oxidative stress interaction should be conducted to
investigate the association [37]. Further research is also required to analyze
how quercetin influences down regulated genes as driving mechanisms for the
clustering of obesity-associated cognitive decline. Additionally, more research
is needed to determine optimum for the quercetin’s positive action. We hope
that the present paper will stimulate further research in this topic and brings
to attention the data that would provide a better understanding of the
management of obesity-induced cognitive decline. Xia’s and colleagues [8]
findings have important public health implications concerning the control by
quercetin of the cognitive decline associated with obesity epidemic [37] and
supporting idea of clinical trials of this relatively safe natural compound. A
better understanding of the mechanisms linking severe obesity to adverse
neurological outcomes is much needed [37]. In conclusion, the present results
indicate that quercetin has protective and detrimental effects on cognition
depending on the diet. Thus, careful consideration must be given to the
evaluation of the redox status of the organism and the in vivo concentration of
quercetin when utilizing dietary quercetin to improve animal and human
cognition. Changes in nutritional status and lifestyle may decrease permanent
damage to cognition health [37]; thus, prevention of obesity should be the goal
by taking antioxidants rather than pharmaceutical treatment. Additionally,
quercetin treatment prevents cognitive dysfunction provoked by chronic stress
induced in rats, which may render quercetin as an effective agent for the
treatment of stress-related disorders [51]. The protective action of quercetin
on cognitive decline may be connected with both reducing the plasma
corticosterone level and its pro-oxidant activity [51]. More research is
required to support quercetin use as a lead particle in its free form in acute
therapies, requiring new pharmacological formula and/or structural modification
to limit its pro-oxidant effect. This fact would limit an acute treatment by
quercetin in spite of its hopeful protective property in vivo and in vitro.
Adjustment of the molecule by changing the harmful hydroxyl groups of the
catechol moiety can reduce the generation of quinones and could be the first
key step to increase its protective activity over the toxic one [52].
Activation of Nrf2, increasing its displacement to the nucleus and facilitating
the formation of proteins against oxidation and pro-survival is especially
important. Increasing glutathione level is a key factor in the restoration of
the redox system in intracellular space [52]. Activation of transcription
factor such as NF-kB and/or molecules for survival, like sirtuins, and kinase
inhibition as well as influence on intracellular signaling seem factors of the
complex pro-survival feature of quercetin [51].
ACKNOWLEDGMENTS
This work
was supported by the Mossakowski Medical Research Centre (T3-RP).
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