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Greasing the wheels of managing overweight and obesity with omega-3 fatty acids
Greasing the wheels of managing overweight and obesity with omega-3 fatty acids q
N. Golub , D. Geba S.A. Mousa , G. Williams , R.C. Block
a The University of Rochester School of Medicine and Dentistry, Rochester, NY, USAb Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USAc Center for Community Health, Department of Medicine, The University of Rochester School of Medicine and Dentistry, Rochester, NY, USAd Department of Community and Preventive Medicine and the Cardiology Division, Department of Medicine, The University of Rochester School of Medicine and Dentistry, Rochester,NY, USA
The epidemic of overweight and obesity around the world and in the US is a major public health chal-
lenge, with 1.5 billion overweight and obese adults worldwide, and 68% of US adults and 31% of US chil-
dren and adolescents overweight or obese. Obesity leads to serious health consequences, including anincreased risk of type 2 diabetes mellitus and heart disease. Current preventive and medical treatmentsinclude lifestyle modiﬁcation, medication, and bariatric surgery in extreme cases; however, they areeither not very efﬁcacious or are very expensive. Obesity is a complex condition involving the dysregu-lation of several organ systems and molecular pathways, including adipose tissue, the pancreas, the gas-trointestinal tract, and the CNS. The role of the CNS in obesity is receiving more attention as obesity ratesrise and treatments continue to fail. While the role of the hypothalamus in regulation of appetite and foodintake has long been recognized, the roles of the CNS reward systems are beginning to be examined as therole of environmental inﬂuences on energy balance are explored.
Omega-3 polyunsaturated fatty acids are essential nutrients that play a beneﬁcial role in several dis-
ease processes due to their anti-inﬂammatory effects, modulation of lipids, and effects on the CNS.
Omega-3 fatty acids, speciﬁcally EPA and DHA, have shown promising preliminary results in animaland human studies in the prevention and treatment of obesity. Given their effects on many of the path-ways involved in obesity, and speciﬁcally in the endocannabinoid and mesocorticolimbic pathways, wehypothesize that EPA and DHA supplementation in populations can reduce the reward associated withfood, thereby reduce appetite and food intake, and ultimately contribute to the prevention or reductionof obesity. If these fatty acids do harbor such potential, their supplementation in many parts of the worldmay hold great promise in reducing the global burden of obesity.
Ó 2011 Elsevier Ltd. All rights reserved.
at epidemic levels since 1997 In 2008, approximately 1 billionadults in the world were overweight, and 500 million were obese
Known from ancient times and considered traditionally a dis-
The World Health Organization (WHO) deﬁnes obesity as a
ease of afﬂuent individuals, obesity is currently highly prevalent
condition of excess body fat to the extent that health is impaired
in both developed and developing regions of the globe . The
In the US, obesity prevalence is at an all-time high, with
number of overweight and obese individuals has increased at an
approximately one-third of adults considered obese .
alarming rate worldwide in the last few decades, being declared
Obesity is commonly measured using body mass index (BMI,
weight/height2). In pediatric populations, BMI values ranging fromthe 85th to the 95th percentile for age and sex deﬁne overweight,
This publication was made possible by Grant No. UL1 RR024160 from the
while values at or above the 95th percentile deﬁne obesity In
National Center for Research Resources (NCRR), a component of the National
adults, the deﬁnition of obesity is based on absolute values of
Institutes of Health (NIH), and the NIH Roadmap for Medical Research. Its contents
BMI, overweight being a BMI between > 25 and 29.9 kg/m2, and ob-
are solely the responsibility of the authors and do not necessarily represent the
ese being a BMI > 30 kg/m2 . National Health and Nutrition
ofﬁcial view of NCRR or NIH. Information on NCRR is available at
Examination Survey (NHANES) data show that between 1970 and
. Information on Re-engineering the Clinical Research Enterprisecan be obtained from
2000, the prevalence of overweight in children aged 2–19 years
in the US increased from 10% to 15%, and the prevalence of obesity
⇑ Corresponding author. Address: Department of Community and Preventive
in this population tripled, from 5% to 15% In adults aged 20–74
Medicine, Box CU 420644, 265 Crittenden Boulevard, Rochester, NY 14642, USA.
years, the prevalence of overweight increased from 31.5% in
1960–1962 to 32.3% in 2005–2006, and the prevalence of obesity
0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
increased from 13.4% to 35.1% in the same time periods . Among
impact on BMI. The authors concluded that there was not enough
adults, a greater proportion of men (41.2%) are overweight com-
evidence that any of the interventions were successful in prevent-
pared to women (28.4%), and women are more likely than men
ing or reducing overweight/obesity, and point to methodological
to be obese or extremely obese Prevalence of overweight
issues in the studies, their short duration, and the complexity of
and obesity is disproportionately higher among individuals of low-
preventing obesity as reasons for lack of efﬁcacy. Another review
er socioeconomic status and among minority groups like African-
of interventions in children aged 0–5 years found similar results
Americans, Hispanics, and Native-Americans While no
Some researchers have emphasized the importance of a
gender differences in obesity prevalence have been observed in
family component to improving the effectiveness of interventions
the pediatric population, the discrepancies according to race/eth-
to reduce overweight and obesity , as well as the greater
nicity and socioeconomic status mirror those of the adult
success of interventions with multiple components that address
the multifactorial causes of obesity A number of studies have
The causes of obesity are multifactorial. Most cases of obesity
examined the prevention or reduction of overweight and obesity in
are caused by the imbalance between energy intake and expendi-
adults, and, as in children, showed inconclusive evidence of efﬁ-
ture and a small proportion of obesity cases are secondary
to medical conditions (e.g., Prader-Willi syndrome or Cushing
Not only is weight loss hard to achieve, but it is even more difﬁ-
syndrome), or are treatment-related (e.g., treatment with antide-
cult to maintain, with most dieters back to baseline weight within
pressants or anticonvulsants). Changes brought by industrializa-
3–5 years from intervention . This suggests that weight loss
tion, with their negative inﬂuences on both diet and physical
interventions need to be not only more sustainable for patient and
activity levels, explain, at least in part, the increasing trends in
medical providers but also better tolerated and physiologically
obesity prevalence seen during the last decades. Like other chronic
effective. While changes at the level of individual behavior are nec-
diseases, the worldwide spread of the obesity epidemic is the
essary in order to prevent overweight and obesity, changes at the
consequence of the fact that it has followed the model of the
policy and societal level are also critical in order to address the avail-
ability of affordable and quality foods, safe and accessible places toengage in physical activity, and other upstream factors .
Concerns raised due to the increasing obesity prevalence are
reﬂected in the growing body of publications in recent yearspertaining to this topic, some articulating theories regarding the
Complications of obesity in adults include dyslipidemia, type 2
multifactorial cause of the disease. While changes over time in lev-
diabetes mellitus, coronary heart disease, hypertension, cancer,
els of physical activity among different segments of the US popula-
and premature death Along with the increasing preva-
tion have played an important role, most sources suggest the
lence of obesity in recent decades, complications of obesity rarely
paramount importance of changes related to diet, including avail-
seen in the pediatric population, such as type 2 diabetes, hyperten-
ability and food costs, food preparation techniques, food composi-
sion, dyslipidemia, cardiovascular disease, and metabolic syn-
tion and diversity, and a progressive replacement of in-home
drome are becoming more common . Consequently, more
cooked meals with ready-to-eat snacks, and restaurant and fast-
high quality and productive life years are lost with the shift of
food meals During a period of 17 years from 1977–1978
these diseases to earlier in the life span . Additionally, the
to 1994–1996, the average daily energy intake increased about
excess weight gained early in life is usually difﬁcult to lose, as
268 calories for men and 143 calories for women While this
overweight and obesity in childhood tracks into adulthood
increase may seem moderate, sustained over time and combined
Based on these considerations, in 2004, the Institute of Medi-
with the effect of other dietary changes and the concomitant
cine introduced its laudable initiative to consider the prevention of
reduction in physical activity at the population level, it provides
obesity in children a national priority .
a plausible explanation for the weight gain observed among Amer-
The multitude of complications from obesity not only causes
human suffering, but also determines the staggering economical
This paper will address appetite and food intake, and their role
costs associated with obesity. Depending on the mathematical
in obesity in the context of great food availability. Appetite and
model used to estimate the costs, they range between about 6%
food intake are two closely related concepts, and are deﬁned in
and 16% of total health care expenditures in the US. Given
the current work as the subjective desire to ingest food, felt as
the relentlessly increasing prevalence of obesity, these costs are
hunger, and the objective physical intake of food, respectively.
likely to increase. Therefore, it is imperative to increase efforts to
We hypothesize that the ingestion of ﬁsh omega-3 fatty acids
address the current obesity epidemic. These efforts should be di-
has the potential of reducing appetite, food intake, and ultimately
rected toward developing and implementing interventions aimed
reducing overweight and obesity. These fatty acids have other
at reducing the prevalence of overweight and obesity in adults
known health beneﬁts and we describe later in this article why
and preventing their development in the pediatric population.
we believe their advantages include the regulation of appetite inpositive ways.
Challenges inherent in reducing overweight and obesity
Appetite and food intake regulation and obesity
Aligned with these strategies, numerous interventions have
been carried out in the pediatric and adult populations, with most
Appetite and food intake are complex processes involving mul-
reporting only marginal success. A recent Cochrane review exam-
tiple organ systems. When food enters the gastrointestinal tract,
ined evidence from 22 randomized controlled trials lasting from
information on pH, gastric stretch, and changes in nutrient compo-
12 weeks to 3 years that aimed to reduce overweight and obesity
sition are relayed by the vagus nerve to several areas of the brain,
in children under 18 years old . The trials were predominantly
including the medulla, hypothalamus, amygdala, and thalamus
school-based and included children ranging from 7 to 12 years old;
These signals are involved in the regulation of feeding. In
some examined the roles of increasing physical activity levels or
addition, the gastrointestinal tract secretes hormones that control
improving diet, and some examined their combined effect on
feeding by acting on the brain. For example, cholecystokinin secre-
BMI. Although most trials found an improvement in the amount
tion is a satiety signal for the brain, and gherlin secretion acts on
of physical activity or healthy eating habits, only a few found an
the hypothalamus to stimulate feeding.
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
A key hormone in appetite and metabolism regulation is leptin,
reward cause release of dopamine in the nucleus accumbens, while
which is released from adipose tissue. The amount of leptin in the
dopaminergic ﬁbers projecting from the nucleus accumbens to the
body is increased by higher fat mass, and decreases with decreased
prefrontal cortex may inhibit this release of dopamine . Other
fat mass. Leptin acts on the hypothalamus to inhibit the orexigenic
systems involved in energy intake can act on the mesocorticolim-
effects of the peptides neuropeptide Y (NPY) and agouti-related
bic dopamine system to modulate food intake. Speciﬁcally, endo-
peptide (AgRP), and activates the anorexigenic effects of down-
cannabinoids act on the nucleus accumbens to increase food
stream targets of pro-opiomelanocortin (POMC) and cocaine-
intake , leptin and insulin can act directly on mesolimbic
amphetamine regulated transcript (CART). Together, this leads to
dopamine neurons, to decrease desire for food and motivation to
satiety, and stimulates energy expenditure and ultimately weight
feed , and opioids and other neurotransmitters such as seroto-
loss. Individuals who are obese have high leptin levels, but have
nin, GABA and glutamate also modulate food reward in various
decreased responsiveness to leptin signaling, also known as leptin
ways The nucleus accumbens shell is critical in coordinating
resistance. Another key hormone in regulation of adiposity is insu-
the effects of opioids, endocannabinoids, and neurotransmitters
lin, which is secreted from the pancreas in response to feeding.
Similar to leptin, insulin acts on the hypothalamus to inhibit NPY
Due to evolutionary forces, there is strict homeostatic control of
and AGRP, and activates POMC and CART, and obese individuals
adiposity in environments of food scarcity, leading to hunger, food
seeking behavior, and decreased energy expenditure . How-
The endocannabinoid pathway is another important player in
ever, there is less control over adiposity in environments of food
regulation of appetite and metabolism . Endocannabinoids
surplus. For example, obesity is characterized by insulin and leptin
are lipids derived from the omega-6 polyunsaturated fatty acid,
resistance. Thus while insulin and leptin levels increase with in-
arachidonic acid. Levels of endocannabinoids are regulated by die-
creased adiposity, their traditional action on the CNS to decrease
tary intake of essential fatty acids, and the activity of biosynthetic
appetite and increase energy expenditure becomes inefﬁcient,
and catabolic enzymes involved in the endocannabinoid pathway
and the individual continues to consume food despite a positive
. Endocannabinoids activate endogenous cannabinoid CB1
energy balance. It is now clear that there is no set point at which
and CB2 receptors in the brain, liver, adipose tissue, and gastroin-
the body senses and responds to excess adiposity by reducing en-
testinal tract . Activation of CB1 receptors in the hypothalamus
ergy intake. This set point may change based on genetic factors and
leads to increased appetite and food intake by inhibiting the
environmental stimuli such as presence, palatability, and amount
anorexigenic signals of corticotrophin-releasing hormone (CRH)
of food. In addition to the homeostatic control of food intake based
and CART, and activating the orexigenic signal of melanin-concen-
on energy demands, there is the ‘‘non-homeostatic’’ control of food
trating hormone (MCH), as well as via other mechanisms
intake due to the smell, visual, taste stimuli, and rewards that food
Recent ﬁndings from mouse studies showed that endocannabi-
provides. These inputs can override homeostatic satiety signals by
noids selectively enhance sweet taste, and this increasing palat-
acting on CNS reward pathways . It is important to note that
ability of foods is hypothesized to stimulate food intake .
regulation of homeostatic and non-homeostatic feeding involves
In addition to their role in the central nervous system (CNS),
reward pathways, and thus there is a complex interplay between
endocannabinoids exert complex effects on peripheral tissues to
these systems and energy intake and expenditure. The current food
control energy homeostasis . For example, they act on adipose
environment in the United States is characterized by the presence
tissue to increase fat accumulation and apidogenesis, and on the
of inexpensive, energy-dense and palatable foods, which allows for
pancreas to affect insulin levels and glucose regulation. The endo-
overconsumption and excess weight gain.
cannabinoid system functions in concert with other systems regu-lating food intake and energy balance, and is regulated by leptin,
insulin, gherlin, cholecystokinin, and other signals. There is grow-ing evidence from animal and human studies that an overactive
Omega-3 fatty acids (n-3 polyunsaturated fatty acids [PUFA])
endocannabinoid system contributes to weight gain and diet-
are a group of fatty acids that are essential components of the hu-
induced obesity , and targeting this system is a strategy
man diet because they cannot be synthesized in amounts sufﬁcient
for weight loss. Results from randomized controlled trials in over-
for health . Three important omega-3 fatty acids are alpha-lin-
weight/obese humans have shown that CB1 receptor antagonists
olenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexae-
such as rimonabant lead to signiﬁcant weight loss after one year
noic acid (DHA). ALA is found in leafy vegetables, walnuts,
of treatment However, increased risk of anxiety, depression,
soybeans, ﬂaxseed, and seed and vegetable oils, and is the ome-
and suicidality in individuals taking CB1 antagonists
ga-3 fatty acid ingested in greatest amount in a typical diet glob-
prompted withdrawal of rimonabant from the market.
ally. Sources of EPA and DHA are fatty ﬁsh such as salmon and
CNS motivation and reward pathways are also critical in the
mackerel, ﬁsh oil supplements, or the conversion of ingested al-
regulation of appetite and food intake . Fulton deﬁnes the con-
pha-linolenic acid to DHA or EPA, though evidence implies that
cept of reward as ‘‘(1) objects or actions that prioritize behaviour
the conversion rate is low . EPA and DHA have many potential
and promote the continuation of ongoing actions, (2) increase
health beneﬁts, with proven beneﬁts in reducing risk of coronary
the behaviours that lead to the procurement and/or consumption
heart disease , and potential beneﬁts in the prevention
of the reward (positive reinforcement), and (3) direct future behav-
and treatment of other cardiovascular disorders some forms
ioural actions’’. Major neurotransmitter pathways involved in
of mental illness inﬂammatory disorders such as rheuma-
reward are the dopaminergic pathways in the CNS The mes-
toid arthritis and insulin resistance .
olimbic pathway sends projections from the ventral tegmental area
Omega-3 fatty acids are important components of cell mem-
to the nucleus accumbens, and the mesocortical pathways send
branes They also play a key role in the development and func-
dopaminergic ﬁbers from the nucleus accumbens to the prefrontal
tion of the brain and CNS. Omega-3s, and especially DHA, are
cortex. These pathways are collectively referred to as the mesocor-
necessary for normal cognitive development and vision. DHA is
ticolimbic dopamine system. The mesocotricolimbic dopamine
highly concentrated in neuronal cell membranes, and as such plays
system is implicated in regulation of feeding, and manipulation
an important role in neurotransmission; its depletion is associated
of dopamine levels in the nucleus accumbens and other portions
with abnormalities in the dopaminergic and serotonergic systems,
of reward circuitry has been shown to affect the reward associated
which are involved in regulation of mood and motivation. Omega-
with food Speciﬁcally, new stimuli or stimuli associated with
3s are also precursors of eicosanoids, which are molecules that
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
have anti-inﬂammatory actions, promote vasodilation of blood
in dopaminergic neurotransmission included reduction in the
vessels, and inhibit platelet aggregation. These effects, as well as
vesicular monoamine transporter in the nucleus accumbens and
omega-3’s modulation of body lipid composition, are key in the
frontal cortex of deﬁcient rats, a decrease in dopamine D2 recep-
protective role that they play in cardiovascular disease.
tors in the frontal cortex and increase in the nucleus accumbens,
Formal recommendations have been made by the American
a decrease in basal dopamine release in the frontal cortex, and an
Heart Association advocating that all adults eat oily ﬁsh as least
increase in the nucleus accumbens. In addition, there was de-
twice each week, and that patients with documented coronary
creased release of dopamine in response to most stimulants of
heart disease consume approximately 1 g of the two ﬁsh-derived
dopamine release (tyramine, amphetamine, GBR12909) in deﬁ-
omega-3 fatty acids EPA and DHA, each day . The American
Heart Association also has recently published recommendations
In reversibility studies, n-3 PUFA deﬁcient rats supplemented
for the ingestion of EPA and DHA by individuals with hypertriglyc-
with n-3 PUFA had signiﬁcantly higher total brain n-3 PUFA com-
pared to deﬁcient animals, and had similar brain n-3 PUFA as con-trol animals maintained on an n-3 PUFA rich diet; similar resultswere obtained for n-3 PUFA levels in the nucleus accumbens and
EPA and DHA effects on animal brain endocannabinoid levels
the hippocampus Deﬁcient rats had a signiﬁcantly lower re-lease of dopamine in response to tyramine compared to supple-
The ability of essential fatty acids to regulate endocannabinoid
mented and control animals in the prefrontal cortex and the
levels raises the question of whether DHA and EPA can affect brain
nucleus accumbens. Supplemented and control animals had simi-
endocannabinoids. For instance, mice chronically deﬁcient in n-3
lar release of dopamine, except animals supplemented with n-3
PUFA have signiﬁcantly lower concentrations of DHA in brain
PUFA for the shortest duration ($40 days), who had a signiﬁcantly
phospholipids, and signiﬁcantly higher brain levels of the endocan-
lower release of dopamine compared to controls, and similar to
nabinoid, arachidonoylglycerol (2-AG), compared to mice with
that of deﬁcient animals. While the n-3 PUFA deﬁciency induced
sufﬁcient n-3 PUFA in the diet . In addition, n-3 PUFA supple-
in these experiments is severe, and thus it is difﬁcult to predict
mentation of 10% weight/weight DHA-rich ﬁsh oil for 4 weeks in
how more physiological changes in n-3 PUFA will affect dopami-
mice led to signiﬁcantly higher brain DHA levels compared to mice
nergic transmission in animals and humans, this evidence does
on a low n-3 PUFA diet, and led to a signiﬁcant decrease in brain
show the potential for dietary n-3 PUFA to affect dopaminergic
2-AG and brain arachidonic acid. In another study, obese rats were
fed for 1 month on a diet supplemented with n-3 PUFA in the form
Chalon et al. concluded that n-3 PUFA deﬁciency may lead to an
of ﬁsh oil or krill oil, at a dose equivalent to 1.8 g/day for a 2000
overactive mesolimbic dopamine system, and a hypofunctional
calorie diet in humans . Rats supplemented with krill oil had
mesocortical pathway, which could manifest in changes in behav-
a signiﬁcantly higher concentration of brain EPA and DHA com-
ior relating to reward, motivation, and learning . Similarly,
pared to controls and the ﬁsh oil group, and had signiﬁcantly lower
Reisbick postulated that the behavioral changes, namely in atten-
levels of 2-AG in the brains compared to controls and the ﬁsh oil
tion, motivation, and reaction to reward seen in n-3 PUFA deﬁcient
group, though food intake was not affected. D’Asti et al. found that
rats are consistent with defects in the mesocorticolimic dopamine
10-day old mice from dams on a high fat diet supplemented with
pathway He proposes that the hypofunction of the mesocor-
n-3 PUFA had marginally lower (p = 0.06) 2-AG levels in the hypo-
tical pathway leads to disinhibition of the mesolimbic pathway,
thalamus, and signiﬁcantly lower 2-AG in the hippocampus com-
resulting in increased dopamine release, and subsequent increased
pared to pups from dams on a control diet and those on a high
reactivity to stimuli. Increased activity in an open-ﬁeld test, faster
fat, high n-6 PUFA diet These studies demonstrate the ability
swimming speeds, and increased time in open arms maze in ro-
of dietary n-3 PUFA supplementation to affect brain DHA, and
dents are cited as supporting this hypothesis.
decrease brain 2-AG levels, even at a fairly low dose that is compa-
In humans, n-3 PUFA deﬁciency is associated with disorders
rable to a safe intake of n-3 PUFAs in humans. The 2-AG has been
involving dysfunction of dopaminergic systems such as attention
shown in animal models of obesity to be involved in overeating
deﬁcit hyperactivity disorder (ADHD), and schizophrenia
and thus these results suggest that dietary n-3 PUFA supple-
ADHD is characterized by impulsivity, hyperactivity, and atten-
mentation may be able to affect food intake by acting to decrease
tional deﬁcits . In addition, changes in response to reinforce-
ment have been described in children with ADHD, demonstratedby a stronger preference for immediate versus delayed reinforce-
EPA and DHA effects on dopaminergic systems
ment, even if the immediate reinforcement is smaller than thedelayed reinforcement . Reviews of studies in humans have
Investigations in animals have demonstrated that n-3 PUFA
demonstrated the involvement of the prefrontal cortex, striatal
deﬁciency leads to changes in performance in several behavioral
reward pathways, and catecholamines (dopamine and noradrena-
tests , such as increased response rates to rewards
line) in ADHD . In fact, it has been proposed that the path-
(including food), and longer extinction times (return of response
ophysiology of ADHD involves impaired inhibition of limbic
to baseline after removal of reward) . These observed differ-
structures by the frontal cortex, and that the efﬁcacy of stimulants
ences could be due to effects on learning, and factors that affect
(that act to increase dopamine levels) in treatment of ADHD may
learning such as sensory and motor abilities, motivation, arousal
be due to their ability to restore proper cortical inhibition
and attention . Some investigators postulate that the increased
Trials examining n-3 PUFA supplementation in individuals with
response to reinforcement and slower extinction may be due to
ADHD are conﬂicting, though some studies do show improvement
changes in motivation in n-3 deﬁcient animals . There is
growing evidence that these changes in n-3 PUFA deﬁcient animals
Schizophrenia is a disorder in which symptoms include halluci-
are in part due to alteration of dopaminergic systems in the brain.
nations, delusions, disorganized speech, catatonic behavior, nega-
Chalon et al. carried out a series of experiments investigating the
tive symptoms such as ﬂat affect and avolition (lack of
effects of chronic n-3 PUFA deﬁciency on dopaminergic neuro-
motivation), and signiﬁcant social and occupational dysfunction
transmission Rats on a diet deﬁcient in ALA, the precursor
. Dysfunction of dopamine signaling in mesocorticolimbic struc-
of n-3 PUFAs, had a 70% reduction in n-3 PUFA in brain phospho-
tures, including the prefrontal cortex, nucleus accumbens, and
lipids, with a subsequent increase in brain n-6 PUFA. Alterations
amygdala is implicated in the pathophysiology of schizophrenia,
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
and treatment involves dopamine D2 receptor antagonists
In obese subjects, there was a signiﬁcant inverse correlation of
Studies of omega-3 fatty acid supplementation have shown promis-
À0.4 between plasma n-3 PUFA and BMI, and correlations of
ing results in alleviating symptoms and reducing likelihood of psy-
À0.27 and À0.41 for waist and hip circumference, respectively
chosis in individuals at high risk of developing schizophrenia, while
In addition, there was a signiﬁcant inverse relationship be-
studies of individuals with established schizophrenia have shown
tween quartiles of plasma n-3 and BMI, waist, and hip circumfer-
conﬂicting results . While ADHD and schizophrenia are very
ence. Studies in youth report signiﬁcantly decreased plasma n-3
complex and differing disorders, there are similarities in terms of
PUFA concentration in overweight youth compared to healthy
the CNS pathways involved and behavioral manifestations to those
youth and in obese youth, plasma n-3 PUFA is signiﬁcantly in-
of animal models of n-3 PUFA deﬁciency, pointing to the key role
versely related to BMI z-score quartiles .
that omega-3 fatty acids may play in the normal functioning of
Randomized controlled trials in humans examining the rela-
the mesocorticolimbic system in humans, and the potential for ome-
tionship between omega-3 supplementation and body composi-
ga-3 supplements to ameliorate dysfunction in this system.
tion have found conﬂicting results . This may be due todifferences in study design, the dosage, timing, and duration of
n-3 PUFA administration, use of other supplements in addition ton-3 PUFA, and demographics of the study population. Studies that
Animal and human studies have shown that EPA and DHA sup-
have provided supporting evidence for a role of n-3 PUFAs in body
plementation may be protective against obesity, and may reduce
weight gain in already obese animals and humans . Speciﬁ-
A study of 2-month n-3 PUFA supplementation in 26 over-
cally, studies demonstrated a reduction in visceral (epidydimal
weight or obese post-menopausal women with diabetes found a
and/or retroperitoneal) fat in rats fed high lipid diets that incorpo-
reduction in body fat mass and a reduction in adipocyte diameter,
rate n-3 PUFAs and the effect was dose-dependent
though no reduction in body weight or total energy intake was
The reduction in visceral fat was associated with a decrease in adi-
seen . An 8-week study of 278 overweight adults found that
pocyte size and number of adipocytes .
those on a restricted calorie diet rich in lean or fatty ﬁsh or ﬁsh
The reduction in visceral fat was seen in some studies without
oil had a signiﬁcant reduction in waist circumference and weight
changes in energy intake , while three studies re-
compared to individuals on a calorie restricted diet, but this effect
ported a signiﬁcantly decreased food intake in rats
was only seen in men . Participants in this study on the high n-
on an n-3 PUFA supplemented diet. On the other hand, perinatal
3 PUFA diets reported more fullness immediately after a test meal
n-3 PUFA deﬁciency in rats has been associated with signiﬁcantly
and more fullness and less hunger 2 h postprandial than those on a
increased food . In addition, a dopamine-DHA conju-
low n-3 PUFA diet . This ﬁnding supports a potential role for
gate was found to increase dopamine transport across the
omega-3 in appetite regulation in humans.
blood–brain barrier of mice by 7.5-fold, and led to about 50%
Hypothesis: EPA and DHA act on the human mesocorticolimbic
reduction in food consumption in mice and rats compared to
pathway and the human endocannabinoid pathway to decrease
control animals; the effect persisted for the 3 week duration of
the reward associated with food, thereby reducing appetite, food
the dopamine–DHA conjugate administration These studies
intake, and ultimately reducing overweight and obesity.
suggest that n-3 PUFA can play a role in regulation of food intake
Different organ systems in the body and various pathways are
involved in appetite, food intake, and energy homeostasis, and
A study of obese rats found that n-3 PUFA supplementation led
the dysregulation of these systems leads to obesity. These include
to a signiﬁcant, reduction in weight gain compared to controls in
brain structures such as the brain stem, hypothalamus, and reward
the lower and higher dose of n3-PUFA (5.9% and 5.1%, respectively,
pathways, as well as the gastrointestinal tract, adipose tissue, and
and rats on the higher dose consumed signiﬁcantly less food com-
the pancreas. Increasing evidence suggests that the omega-3 fatty
pared to controls Ruzickova et al. demonstrated an attenua-
acids EPA and DHA play a role in these organ systems, and espe-
tion of weight gain in mice on a high fat diet supplemented with
cially in the CNS. Studies in animals and humans have shown
n-3 PUFA, and even weight loss in those on the highest concentra-
promising effects of treatment with EPA/DHA supplemented diets
tion of n3-PUFA. Similarly, aged rats on a high n-3 PUFA diet for
to prevent and reduce obesity. These positive effects have mostly
4 months had a signiﬁcantly lower body weight compared to those
been discussed in the realm of the effect of EPA and DHA on met-
abolic proﬁles of subjects, i.e., reductions in visceral fat, greater
There is promising evidence in animal studies that n-3 PUFA
insulin sensitivity, and improvements in lipid proﬁles. While the
supplementation can modulate fat deposition, food intake, and
effects of EPA/DHA on the endocannabinoid system and on dopa-
body weight. However, we should use caution when making infer-
minergic reward systems in the brain have been described, to
ences to the effects of n-3 PUFA in humans, because of possible dif-
our knowledge, no animal or human studies have examined the
ferences in pharmacokinetics of EPA and DHA supplementation
role of DHA and EPA in modulating these systems to affect appetite
between animals and humans, and because the doses used in ani-
and food intake. As the endocannabinoid and mesocorticolimbic
mal studies vary widely and are typically higher than those
pathways play a role in appetite, energy intake and obesity, we
considered safe in humans. For example, Perez-Matute et al. used
hypothesize that, in addition to beneﬁcial effects on metabolism,
a dose of 1 g/kg/day EPA in rats, while Takahashi and Ide used
EPA and DHA regulate the endocannabinoid and mesocorticolimbic
85.2 g/kg/day EPA + DHA in rats . A dosage of 1 g/kg/day
dopamine systems in humans to decrease appetite, increase sati-
in rats corresponds to 9.6 g/day in a 60 kg person The average
ety, reduce food intake, and ultimately contribute to prevention
intake of omega-3s in the US is approximately 1.6 g/day ($0.7% of
or reduction of overweight and obesity. Supporting evidence for
energy intake), with 1.4 g of ALA and .2 g of EPA/DHA The
Food and Drug Administration deems intake of up to 3 g/day ofmarine omega-3s as ‘‘generally recognized as safe’’ .
(1) EPA and DHA supplementation decreases brain endocannab-
Fewer studies have examined the association between n-3 PUFA
intake and adiposity in humans. An observational study of 124
(2) EPA and DHA deﬁciency is associated with dysfunction of
adults found that obese individuals had signiﬁcantly lower plasma
the mesocorticolimbic system in animals, and with behav-
n-3 PUFA concentration compared to healthy weight participants.
ioral changes including motivation and response to reward.
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
(3) EPA and DHA supplementation has been shown to affect
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5-HTP - 5-Hydroxytryptophan aus Griffonia Simplicifolia Hilft beim natürlichen Einschlafen. Verringert die Schmerzempfindlichkeit. Wirkt als natürliches Mittel gegen Depressionen. Lindert Migränekopfschmerzen. Hilft bei der Verminderung von Angst und Stress. Hilft bei der Linderung einiger Symptome von biologischen Störungen im Körper, die durch Alkohol ausgelöst werden, und ist e
Gamal Abd El-Khalek El-Azab PERSONAL INFORMATION WORK HISTORY Associate Prof. Clinical Pharmacy and Hospital Pharmacy Dept. Prof. Ass. , clinical pharmacy Dept, King Saudi Univ. school of Prof. Ass. , clinical pharmacy Dept, King Saudi Univ. school of pharmacy Saudi Arabia. Professor visitor of clinical pharmacy Dept. School of Pharmacy and medical sciences , Amman University, Am