Impotentie brengt een constant ongemak met zich mee, net als fysieke en psychologische problemen in uw leven cialis kopen terwijl generieke medicijnen al bewezen en geperfectioneerd zijn
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
 Anderson PM, Butcher KE. Childhood obesity: trends and potential causes.
dopaminergic transmission in animals, and has shown some
 Wang Y, Beydoun MA. The obesity epidemic in the United States – gender,
preliminary evidence of efﬁcacy in modulating symptoms in
humans with disorders of the mesocorticolimbic system.
(4) EPA/DHA supplementation affects the modulation of appe-
 Kuntz B, Lampert T. Socioeconomic factors and obesity. Dtsch Arztebl Int
tite and food intake in some animal and human studies.
(5) EPA/DHA supplementation reduces fat mass, and in some
 Quilliot D, Roche G, Mohebbi H, Sirvaux MA, Bohme P, Ziegler O. Nonsurgical
cases, weight gain, in animal and human studies.
management of obesity in adults. Presse Med 2010;39:930–44.
 Robinson TN. Television viewing and childhood obesity. Pediatr Clin North
Further studies are necessary to elucidate the effects of EPA/
 Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular
DHA supplementation on the reward associated with food intake
diseases: part I: general considerations, the epidemiologic transition, riskfactors, and impact of urbanization. Circulation 2001;104:2746–53.
and appetite, food consumption, weight loss, and, at the same time,
 Omran AR. The epidemiologic transition: a theory of the epidemiology of
the molecular effects on the function of the endocannabinoid sys-
population change, 1971. Milbank Q 2005;83:731–57.
tem and the mesocorticolimbic system. Studies in humans are
 Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet
especially key, because molecular and behavioral changes in ani-
 Mokdad AH, Ford ES, Bowman ES, et al. Prevalence of obesity, diabetes, and
mal models may not correspond to the same effects in humans.
obesity-related health risk factors, 2001. JAMA 2003;289:76–9.
In addition, the interplay between diets of differing composition
 McElroy SL, Kotwal R, Malhotra S, Nelson EB, Keck PE, Nemeroff CB. Are mood
of essential fatty acids and effects of EPA/DHA must be examined
disorders and obesity related? A review for the mental health professional. JClin Psychiatry 2004;65:634–51 [quiz 730].
because the effects of n-3 PUFAs also depend on the ratio of n-3
 Woolf AD, Breedveld F, Kvien TK. Controlling the obesity epidemic is
to n-6 fatty acids, as they are substrates that compete for some
important for maintaining musculoskeletal health. Ann Rheum Dis
 Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of
Given the continuing rise in the worldwide rates of overweight
overweight to cardiovascular risk factors among children and adolescents:
and obesity, with failure of current prevention and treatment par-
the Bogalusa Heart Study. Pediatrics 1999;103:1175–82.
adigms, exploration of other avenues of prevention and treatment
 Marcovecchio M, Mohn A, Chiarelli F. Type 2 diabetes mellitus in children and
adolescents. J Endocrinol Invest 2005;28:853–63.
is needed. Increasing omega-3 fatty acid intake via changes in diet
 James PT, Rigby N, Leach R. The obesity epidemic, metabolic syndrome and
or via supplementation with ﬁsh oil may be one strategy. Although
future prevention strategies. Eur J Cardiovasc Prev Rehabil 2004;11:3–8.
evidence for a role of omega-3 fatty acids in prevention of over-
 Galal OM, Hulett J. Obesity among schoolchildren in developing countries.
weight and obesity is just beginning to be accumulated, the various
 Field AE, Cook NR, Gillman MW. Weight status in childhood as a predictor of
other health beneﬁts and lack of negative side effects warrant con-
becoming overweight or hypertensive in early adulthood. Obes Res
sideration of the need to encourage dietary changes to increase n-3
PUFA or the use of n-3 PUFA supplements at the population level.
 Nader PR, O’Brien M, Houts R, et al. Identifying risk for obesity in early
childhood. Pediatrics 2006;118:e594–601.
Even if the effect of n-3 PUFA on overweight and obesity is found to
 Herman KM, Craig CL, Gauvin L, Katzmarzyk PT. Tracking of obesity and
be small, such changes at the level of the individual can lead to sig-
physical activity from childhood to adulthood: the Physical Activity
niﬁcant shifts in the distribution of weight in the population .
Longitudinal Study. Int J Pediatr Obes 2009;4:281–8.
 Koplan JP, Liverman CT, Kraak VI. Preventing childhood obesity: health in the
In addition, since ﬁsh oil is inexpensive, safe , and few interac-
balance: executive summary. J Am Diet Assoc 2005;105:131–8.
tions with pharmaceutical drugs exist this approach is poten-
 Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the
tially very viable as a public health intervention.
United States. Obes Res 1998;6:97–106.
 Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental
variables approach. 2010. Accessed July 1, 2011
 Summerbell CD, Waters E, Edmunds LD, Kelly S, Brown T, Campbell LD.
Interventions for preventing obesity in children. Cochrane Database Syst Rev
The authors declare that they have no conﬂict of interest.
 Campbell KJ, Hesketh KD. Strategies which aim to positively impact on
weight, Physical activity, diet and sedentary behaviours in children from
zero to ﬁve years. A systematic review of the literature. Obes Rev2007;8:327–38.
 Hesketh KD, Campbell KJ. Interventions to prevent obesity in 0-5 year olds:
The authors would like to thank Kelly Keating, PhD, at the
an updated systematic review of the literature. Obesity (Silver Spring)
Albany College of Pharmacy and Health Sciences, for her assistance
 Young KM, Northern JJ, Lister KM, Drummond JA, O’Brien WH. A meta-
analysis of family-behavioral weight-loss treatments for children. ClinPsychol Rev 2007;27:240–9.
 Seo DC, Sa J. A meta-analysis of obesity interventions among U.S. minority
children. J Adolesc Health 2010;46:309–23.
 Lombard CB, Deeks AA, Teede HJ. A systematic review of interventions aimed
 de Moraes AC, Fadoni RP, Ricardi LM, et al. Prevalence of abdominal obesity in
adolescents: a systematic review. Obes Rev 2011;12:69–77.
 Misra A, Khurana L. Obesity and the metabolic syndrome in developing
 Lemmens VE, Oenema A, Klepp KI, Henriksen HB, Brug J. A systematic review
countries. J Clin Endocrinol Metab 2008;93:S9–S30.
of the evidence regarding efﬁcacy of obesity prevention interventions among
 World Health Organization (WHO). Obesity: preventing and managing the
global epidemic. Report of a WHO consultation. World Health Organ Tech Rep
 Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL. A self-regulation program for
maintenance of weight loss. N Engl J Med 2006;355:1563–71.
 World Health Organization (WHO). Obesity and overweight. 2011. Accessed
 Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, ﬁsh oil, omega-3
 Garrow JS. Obesity and related diseases. London: Churchill Livingstone; 1988.
 Center for Health Statistics (NCHS). Prevalence of overweight, obesity, and
 Caterson ID, Gill TP. Obesity: epidemiology and possible prevention. Best
extreme obesity among adults: United States, trends 1976–80 through 2005–
Pract Res Clin Endocrinol Metab 2002;16:595–610.
2006. 2008. Accessed April 20, 2010 http://www.cdc.gov/nchs/data/hestat/
 Nielsen SJ, Siega-Riz AM, Popkin BM. Trends in energy intake in U.S. between
1977 and 1996: similar shifts seen across age groups. Obes Res
 Center for Disease Control and Prevention (CDC). About BMI for children and
 Cutler DM, Glaeser EL, Shapiro JL. Why have Americans become more obese? J
 Center for Disease Control and Prevention (CDC). About BMI for adults. 2009.
 Ahima RS, Antwi DA. Brain regulation of appetite and satiety. Endocrinol
Metab Clin North Am 2008;37:811–23.
N. Golub et al. / Medical Hypotheses 77 (2011) 1114–1120
 Banni S, Di Marzo V. Effect of dietary fat on endocannabinoids and related
 Faraone SV, Biederman J. Neurobiology of attention-deﬁcit hyperactivity
mediators: consequences on energy homeostasis, inﬂammation and mood.
disorder. Biol Psychiatry 1998;44:951–8.
 Artmann A, Petersen G, Hellgren LI, et al. Inﬂuence of dietary fatty acids on
endocannabinoid and N-acylethanolamine levels in rat brain, liver and small
 Laviolette SR. Dopamine modulation of emotional processing in cortical and
intestine. Biochim Biophys Acta 2008;1781:200–12.
subcortical neural circuits: evidence for a ﬁnal common pathway in
 Matias I, Di Marzo V. Endocannabinoids and the control of energy balance.
schizophrenia? Schizophr Bull 2007;33:971–81.
Trends Endocrinol Metab 2007;18:27–37.
 Yoshida R, Ohkuri T, Jyotaki M, et al. Endocannabinoids selectively enhance
polyunsaturated fatty acids. Obes Rev 2009;10:648–59.
sweet taste. Proc Natl Acad Sci USA 2010;107:935–9.
 Hainault I, Carolotti M, Hajduch E, Guichard C, Lavau M. Fish oil in a high lard
 Van Gaal L, Pi-Sunyer X, Despres JP, McCarthy C, Scheen A. Efﬁcacy and safety
diet prevents obesity, hyperlipemia, and adipocyte insulin resistance in rats.
of rimonabant for improvement of multiple cardiometabolic risk factors in
overweight/obese patients: pooled 1-year data from the Rimonabant in
 Baillie RA, Takada R, Nakamura M, Clarke SD. Coordinate induction of
Obesity (RIO) program. Diabetes Care 2008;31(Suppl 2):S229–240.
peroxisomal acyl-CoA oxidase and UCP-3 by dietary ﬁsh oil: a mechanism for
 Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efﬁcacy and
decreased body fat deposition. Prostaglandins Leukot Essent Fatty Acids
safety of the weight-loss drug rimonabant: a meta-analysis of randomised
 Belzung F, Raclot T, Groscolas R. Fish oil n-3 fatty acids selectively limit the
 Fulton S. Appetite and reward. Front Neuroendocrinol 2010;31:85–103.
hypertrophy of abdominal fat depots in growing rats fed high-fat diets. Am J
 Reisbick S, Neuringe M. Omega-3 fatty acid deﬁciency and behavior: a critical
review and directions for future research. In: Yehuda S, Mostofsky DI, editors.
 Parrish CC, Pathy DA, Angel A. Dietary ﬁsh oils limit adipose tissue
Handbook of essential fatty acid biology: biochemistry, physiology and
hypertrophy in rats. Metabolism 1990;39:217–9.
behavioral neurobiology. Towota, NJ: Humana Press; 1997.
 Perez-Matute P, Perez-Echarri N, Martinez JA, Marti A, Moreno-Aliaga MJ.
 Kirkham TC. Endocannabinoids in the regulation of appetite and body weight.
Eicosapentaenoic acid actions on adiposity and insulin resistance in control
and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis
 Figlewicz DP, Benoit SC. Insulin, leptin, and food reward: update 2008. Am J
factor-alpha. Br J Nutr 2007;97:389–98.
Physiol Regul Integr Comp Physiol 2009;296:R9–R19.
 Ruzickova J, Rossmeisl M, Prazak T, et al. Omega-3 PUFA of marine origin limit
 Zheng H, Lenard NR, Shin AC, Berthoud HR. Appetite control and energy
diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids
balance regulation in the modern world: reward-driven brain overrides
repletion signals. Int J Obes (Lond) 2009;33(Suppl 2):S8–S13.
 Huang XF, Xin X, McLennan P, Storlien L. Role of fat amount and type in
 Anderson BM, Ma DW. Are all n-3 polyunsaturated fatty acids created equal?
ameliorating diet-induced obesity: insights at the level of hypothalamic
arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin
 Wang C, Harris WS, Chung M, et al. n-3 fatty acids from ﬁsh or ﬁsh-oil
mRNA expression. Diabetes Obes Metab 2004;6:35–44.
supplements, but not alpha-linolenic acid, beneﬁt cardiovascular disease
 Takahashi Y, Ide T. Dietary n-3 fatty acids affect mRNA level of brown adipose
outcomes in primary- and secondary-prevention studies: a systematic
tissue uncoupling protein 1, and white adipose tissue leptin and glucose
review. Am J Clin Nutr 2006;84:5–17.
transporter 4 in the rat. Br J Nutr 2000;84:175–84.
 Skerrett PJ, Hennekens CH. Consumption of ﬁsh and ﬁsh oils and decreased
risk of stroke. Prev Cardiol 2003;6:38–41.
 Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty
postprandial lipaemia and the associated inﬂammatory response in the
acids for indicated prevention of psychotic disorders: a randomized, placebo-
obese JCR:LA-cp rat. Diabetes Obes Metab 2010;12:139–47.
controlled trial. Arch Gen Psychiatry 2010;67:146–54.
 Mathai ML, Soueid M, Chen N, et al. Does perinatal omega-3 polyunsaturated
 Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for
fatty acid deﬁciency increase appetite signaling? Obes Res 2004;12:1886–94.
mental illness: which disorder and which fatty acid? Lipids Health Dis
 Shashoua VE, Hesse GW. N-docosahexaenoyl, 3 hydroxytyramine: a
dopaminergic compound that penetrates the blood-brain barrier and
 Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from ﬁsh: the anti-
suppresses appetite. Life Sci 1996;58:1347–57.
inﬂammatory potential of long-chain omega-3 fatty acids. Nutr Rev
 Cha SH, Fukushima A, Sakuma K, Kagawa Y. Chronic docosahexaenoic acid
intake enhances expression of the gene for uncoupling protein 3 and affects
 Carpentier YA, Portois L, Malaisse WJ. n-3 fatty acids and the metabolic
pleiotropic mRNA levels in skeletal muscle of aged C57BL/6NJcl mice. J Nutr
syndrome. Am J Clin Nutr 2006;83:1499S–504S.
 Schuchardt JP, Huss M, Stauss-Grabo M, Hahn A. Signiﬁcance of long-chain
 Food and Drug Administration (FDA). Guidance for industry: estimating the
polyunsaturated fatty acids (PUFAs) for the development and behaviour of
maximum safe starting dose in initial clinical trials for therapeutics in
children. Eur J Pediatr 2010;169:149–64.
adult healthy volunteers. 2005, Accessed April 1, 2011
 Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and Cardiovascular
disease: a scientiﬁc statement from the American Heart Association.
 Kris-Etherton PM, Taylor DS, Yu-Poth S, et al. Polyunsaturated fatty acids in
 Watanabe S, Doshi M, Hamazaki T. n-3 polyunsaturated fatty acid (PUFA)
the food chain in the United States. Am J Clin Nutr 2000;71:179S–88S.
 Food and Drug Administration (FDA). Substances afﬁrmed as generally
arachidonoylglycerol level in mice. Prostaglandins Leukot Essent Fatty
recognized as safe: menhaden oil. Fed Reg 1997;62:30751–7.
 Micallef M, Munro I, Phang M, Garg M. Plasma n-3 polyunsaturated fatty
 Di Marzo V, Griinari M, Carta G, et al. Dietary krill oil increases
acids are negatively associated with obesity. Br J Nutr 2009;102:1370–4.
docosahexaenoic acid and reduces 2-arachidonoylglycerol but not N-
 Klein-Platat C, Drai J, Oujaa M, Schlienger JL, Simon C. Plasma fatty acid
acylethanolamine levels in the brain of obese Zucker rats. Int Dairy J
composition is associated with the metabolic syndrome and low-grade
inﬂammation in overweight adolescents. Am J Clin Nutr 2005;82:1178–84.
 D’Asti E, Long H, Tremblay-Mercier J, et al. Maternal dietary fat determines
 Scaglioni S, Verduci E, Salvioni M, et al. Plasma long-chain fatty acids and the
metabolic proﬁle and the magnitude of endocannabinoid inhibition of the
degree of obesity in Italian children. Acta Paediatr 2006;95:964–9.
stress response in neonatal rat offspring. Endocrinol 2010;151:1685–94.
 Kabir M, Skurnik G, Naour N, et al. Treatment for 2 mo with n 3
 Chalon S, Vancassel S, Zimmer L, Guilloteau D, Durand G. Polyunsaturated
polyunsaturated fatty acids reduces adiposity and some atherogenic factors
but does not improve insulin sensitivity in women with type 2 diabetes: a
neurotransmission. Lipids 2001;36:937–44.
randomized controlled study. Am J Clin Nutr 2007;86:1670–9.
 Fedorova I, Salem Jr N. Omega-3 fatty acids and rodent behavior.
 Thorsdottir I, Tomasson H, Gunnarsdottir I, et al. Randomized trial of weight-
Prostaglandins Leukot Essent Fatty Acids 2006;75:271–89.
loss-diets for young adults varying in ﬁsh and ﬁsh oil content. Int J Obes
 Chalon S. Omega-3 fatty acids and monoamine neurotransmission.
Prostaglandins Leukot Essent Fatty Acids 2006;75:259–69.
 Parra D, Ramel A, Bandarra N, Kiely M, Martinez JA, Thorsdottir I. A diet rich in
 Peet M. Omega-3 polyunsaturated fatty acids in the treatment of
long chain omega-3 fatty acids modulates satiety in overweight and obese
schizophrenia. Isr J Psychiatry Relat Sci 2008;45:19–25.
volunteers during weight loss. Appetite 2008;51:676–80.
 American Psychiatric Association (APA). Diagnostic and statistical manual of
 Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects of
mental disorders DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric
n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism.
 Hill JO. Can a small-changes approach help address the obesity epidemic? A
report of the joint task force of the American Society for Nutrition, Institute of
 Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of
Food Technologists, and International Food Information Council. Am J Clin
dopamine and noradrenaline in the pathophysiology and treatment of
attention-deﬁcit/hyperactivity disorder. Biol Psychiatry 2011;69:e145–57.
 Davidson MH, Stein EA, Bays HE, et al. Efﬁcacy and tolerability of adding
 Prince J. Catecholamine dysfunction in
disorder: an update. J Clin Psychopharmacol 2008;28:S39–45.
placebo-controlled study. Clin Ther 2007;29:1354–67.
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