Animal and human studies have shown that EPA and DHA supplementation may be protective against obesity, and may reduce weight gain in already obese animals and humans [77
]. Specifically, studies demonstrated a reduction in visceral (epidydimal and/or retroperitoneal) fat in rats fed high lipid diets that incorporate n-3 PUFAs [78
], and the effect was dose-dependent [80
The reduction in visceral fat was associated with a decrease in adipocyte size [80
] and number of adipocytes [83
]. The reduction in visceral fat was seen in some studies without changes in energy intake [78
], while 3 studies reported a significantly decreased food intake[82
] in rats on an n-3 PUFA supplemented diet. On the other hand, perinatal n-3 PUFA deficiency in rats has been associated with significantly increased food intake[87
]. In addition, a dopamine-DHA conjugate was found to increase dopamine transport across the blood-brain barrier of mice by 7.5-fold, and led to about 50% reduction in food consumption in mice and rats compared to control animals; the effect persisted for the 3 week duration of the dopamine-DHA conjugate administration [88
]. These studies suggest that n-3 PUFA can play a role in regulation of food intake in rodents.
A study of obese rats found that n-3 PUFA supplementation led to a significant, reduction in weight gain compared to controls in the lower and higher dose of n3-PUFA (5.9% and 5.1%, respectively, and rats on the higher dose consumed significantly less food compared to controls [86
]. Ruzickova et al. demonstrated an attenuation of weight gain in mice on a high fat diet supplemented with n-3 PUFA, and even weight loss in those on the highest concentration of n3-PUFA. Similarly, aged rats on a high n-3 PUFA diet for 4 months had a significantly lower body weight compared to those on a diet high in omega-6 fatty acids [89
There is promising evidence in animal studies that n-3 PUFA supplementation can modulate fat deposition, food intake, and body weight. However, we should use caution when making inferences to the effects of n-3 PUFA in humans, because of possible differences in pharmacokinetics of EPA and DHA supplementation between animals and humans, and because the doses used in animal studies[77
] vary widely and are typically higher than those considered safe in humans. For example, Perez-Matute et al. used a dose of 1g/kg/day EPA in rats, while Takahashi and Ide used 85.2 g/kg/day EPA + DHA in rats [82
]. A dosage of 1g/kg/day in rats corresponds to 9.6g/day in a 60 kg person[90
]. The average intake of omega- 3s in the US is approximately 1.6 grams/day (~.7% of energy intake), with 1.4 g of ALA and .2 g of EPA/DHA [91
]. The Food and Drug Administration deems intake of up to 3 g/day of marine omega-3s as “generally recognized as safe” [92
Fewer studies have examined the association between n-3 PUFA intake and adiposity in humans. An observational study of 124 adults found that obese individuals had significantly lower plasma n-3 PUFA concentration compared to healthy weight participants. In obese subjects, there was a significant inverse correlation of −.4 between plasma n-3 PUFA and BMI, and correlations of −.27 and −.41 for waist and hip circumference, respectively [93
]. In addition, there was a significant inverse relationship between quartiles of plasma n-3 and BMI, waist, and hip circumference. Studies in youth report significantly decreased plasma n-3 PUFA concentration in overweight youth compared to healthy youth [94
], and in obese youth, plasma n-3 PUFA is significantly inversely related to BMI z-score quartiles [95
Randomized controlled trials in humans examining the relationship between omega-3 supplementation and body composition have found conflicting results[77
]. This may be due to differences in study design, the dosage, timing, and duration of n-3 PUFA administration, use of other supplements in addition to n-3 PUFA, and demographics of the study population. Studies that have provided supporting evidence for a role of n-3 PUFAs in body composition are summarized below.
A study of 2-month n-3 PUFA supplementation in 26 overweight or obese postmenopausal women with diabetes found a reduction in body fat mass and a reduction in adipocyte diameter, though no reduction in body weight or total energy intake was seen [96
]. An 8-week study of 278 overweight adults found that those on a restricted calorie diet rich in lean or fatty fish or fish oil had a significant reduction in waist circumference and weight compared to individuals on a calorie restricted diet, but this effect was only seen in men [97
]. Participants in this study on the high n-3 PUFA diets reported more fullness immediately after a test meal and more fullness and less hunger 2 hours postprandial than those on a low n-3 PUFA diet [98
]. This finding supports a potential role for omega-3 in appetite regulation in humans.
HYPOTHESIS: EPA and DHA act on the human mesocorticolimbic pathway and the human endocannabinoid pathway to decrease the reward associated with food, thereby reducing appetite, food intake, and ultimately reducing overweight and obesity
Different organ systems in the body and various pathways are involved in appetite, food intake, and energy homeostasis, and the dysregulation of these systems leads to obesity. These include brain structures such as the brain stem, hypothalamus, and reward pathways, as well as the gastrointestinal tract, adipose tissue, and the pancreas. Increasing evidence suggests that the omega-3 fatty acids EPA and DHA play a role in these organ systems, and especially in the CNS. Studies in animals and humans have shown promising effects of treatment with EPA/DHA supplemented diets to prevent and reduce obesity. These positive effects have mostly been discussed in the realm of the effect of EPA and DHA on metabolic profiles of subjects, i.e., reductions in visceral fat, greater insulin sensitivity, and improvements in lipid profiles. While the effects of EPA/DHA on the endocannabinoid system and on dopaminergic reward systems in the brain have been described, to our knowledge, no animal or human studies have examined the role of DHA and EPA in modulating these systems to affect appetite and food intake. As the endocannabinoid and mesocorticolimbic pathways play a role in appetite, energy intake and obesity, we hypothesize that, in addition to beneficial effects on metabolism, EPA and DHA regulate the endocannabinoid and mesocorticolimbic dopamine systems in humans to decrease appetite, increase satiety, reduce food intake, and ultimately contribute to prevention or reduction of overweight and obesity. Supporting evidence for this hypothesis includes:
- EPA and DHA supplementation decreases brain endocannabinoid levels in rodents.
- EPA and DHA deficiency is associated with dysfunction of the mesocorticolimbic system in animals, and with behavioral changes including motivation and response to reward.
- EPA and DHA supplementation has been shown to affect dopaminergic transmission in animals, and has shown some preliminary evidence of efficacy in modulating symptoms in humans with disorders of the mesocorticolimbic system.
- EPA/DHA supplementation affects the modulation of appetite and food intake in some animal and human studies.
- EPA/DHA supplementation reduces fat mass, and in some cases, weight gain, in animal and human studies.
Further studies are necessary to elucidate the effects of EPA/DHA supplementation on the reward associated with food intake and appetite, food consumption, weight loss, and, at the same time, the molecular effects on the function of the endocannabinoid system and the mesocorticolimbic system. Studies in humans are especially key, because molecular and behavioral changes in animal models may not correspond to the same effects in humans. In addition, the interplay between diets of differing composition of essential fatty acids and effects of EPA/DHA must be examined because the effects of n-3 PUFAs also depend on the ratio of n-3 to n-6 fatty acids, as they are substrates that compete for some of the same enzymes[99
Given the continuing rise in the worldwide rates of overweight and obesity, with failure of current prevention and treatment paradigms, exploration of other avenues of prevention and treatment is needed. Increasing omega-3 fatty acid intake via changes in diet or via supplementation with fish oil may be one strategy. Although evidence for a role of omega-3 fatty acids in prevention of overweight and obesity is just beginning to be accumulated, the various other health benefits and lack of negative side effects warrant consideration of the need to encourage dietary changes to increase n-3 PUFA or the use of n-3 PUFA supplements at the population level. Even if the effect of n-3 PUFA on overweight and obesity is found to be small, such changes at the level of the individual can lead to significant shifts in the distribution of weight in the population[100
]. In addition, since fish oil is inexpensive, safe[38
], and few interactions with pharmaceutical drugs exist[101
] this approach is potentially very viable as a public health intervention.