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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.
doi: 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.
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