An increase in adiposity is associated with altered levels of biologically active proteins. These include the hormones adiponectin and leptin. The marked change in circulating concentrations of these hormones in obesity has been associated with the development of insulin resistance and metabolic syndrome. Variations in dietary lipid consumption have also been shown to impact obesity. Specifically, omega-3 fatty acids have been correlated with the prevention of obesity and subsequent development of chronic disease sequalae. This review explores animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin, considering plausible mechanisms and potential implications for obesity management. Current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects. This may pose benefits in the prevention of weight regain in these subjects following calorie restriction.
Adipocytes produce a number of different proteins, known as adipokines, that have specific biological activities.1, 2 Adipose tissue can regulate energy homeostasis through the action of the secreted adipokines. These include the hormones adiponectin and leptin.3 Altered levels of adiponectin and leptin are correlated with obesity and cardiovascular disease (CVD).4, 5 Adiponectin is negatively correlated with obesity, with lower levels associated with increased risk of death or myocardial infarction (MI).6 Conversely, leptin levels are positively correlated with obesity,7 with high levels identified as an independent risk factor for CVD.8
Adiponectin is a 244 amino-acid protein that has many regulatory actions on energy homeostasis, modulating glucose and lipid metabolism, promoting fatty acid oxidation and enhancing insulin sensitivity in the liver and within skeletal muscle.1, 9, 10, 11 Increased adiponectin levels were initially associated with increased mortality in CVD; however, more recent findings suggest that this may be as a result of a protective effect in cardiovascular conditions, leading to compensatory upregulation in this hormone.12 The marked difference in plasma adiponectin concentrations between non-obese and obese individuals stimulated additional interest in the molecule and the formation of numerous hypotheses regarding its role in the hastened development of vascular disease associated with obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM).5 Decreased circulating levels of adiponectin in obesity have been associated with an increased risk of coronary artery disease9, 13 and MI.14
Human leptin consists of a 146 amino-acid protein with a molecular mass of 16.0 kDa.2 Expression and secretion of this hormone is positively correlated with fat mass15, 16 and adipocyte size.17 Cortisol and insulin both stimulate leptin expression.18 Leptin was originally considered an anti-obesity hormone due to its experimental effects on metabolism and food intake, in that it was observed to decrease food intake and increase energy expenditure in rodents.19 These findings were expanded with reports that plasma leptin concentrations are directly proportional to mean food intake over a period of days or weeks.20, 21 Thus, a decrease in plasma leptin concentration serves as a short-term adaptation to starvation or fasting.20 Correspondingly, leptin levels decrease significantly following dietary or lifestyle-induced weight loss.22, 23
In non-obese individuals, leptin acts via hypothalamic receptors to inhibit feeding and increase thermogenesis.24 Reduced levels result in decreased central sympathetic nervous outflow and mobilization of energy stores via stimulation of glucocorticoid secretion.25 Obese individuals have higher plasma leptin concentrations, though in this case, elevated leptin does not induce the expected reduction in food intake and increase in energy expenditure. This suggests that obese individuals become resistant to the effects of endogenous leptin.25, 26 Hyperleptinemia has been associated with alterations in cytokine signalling,8 including increased production of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNFα)27 and C-reactive protein (CRP),28 and it has also been shown to promote platelet aggregation and thrombosis.29, 30
The quality and quantity of dietary lipid consumption has also been shown to contribute to the current obesity epidemic.31, 32, 33, 34 By influencing the production of adipokines, dietary lipids subsequently impact upon satiety and adiposity.31, 33 In particular, higher plasma levels of omega-3 fatty acids are associated with a lower body mass index (BMI), waist circumference and hip circumference, suggesting that these fatty acids may contribute to a healthy weight status and the prevention of abdominal adiposity.35 Both animal and human studies have reported lower insulin levels in the presence of marine lipid-derived omega-3 fatty acids,36, 37 as well as decreased mortality and cardiovascular incidents.38, 39, 40, 41
An estimated $33.9 billion is spent annually on alternative medicine in United States of America alone.42 Of this, $14.8 billion was accounted for by nutritional supplements.42 Omega-3 supplements (including fish oils) were reported as the most common nonvitamin/nonmineral product taken by adults,43 accounting for 37% of respondents who had utilised natural products in the last 30 days according to the National Health Interview Survey (2007).43 Research supports the benefits of these fatty acids in a number of the co-morbidities of obesity, including CVD39 and T2DM.44 It may therefore be asked whether intake of omega-3 fatty acids will also have a role in the prevention of the development and progression of obesity itself.
Essential fatty acids in health
Essential fatty acids (for example, omega-3 and omega-6) are necessary for the general maintenance of optimal health.45 Marine lipids (for example, sardines, anchovies) are the richest dietary source of omega-3 fatty acids, including the polyunsaturated fatty acids (PUFA), docosaexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Humans are unable to synthesise sufficient quantities of these fatty acids.39 Acquisition is primarily from dietary or supplementary sources.
Omega-3 vs omega-6 fatty acids
In Western diets, omega-6 fatty acids are the predominant form of polyunsaturated fats. Dietary sources of omega-6 (linoleic acid and arachadonic acid) include poultry, eggs, nuts, cereals, whole grains and most vegetable oils. Figure 1 demonstrates the metabolically distinct and opposing physiological function of omega-3 and omega-6 fatty acids.46
Omega-3 and omega-6 fatty acids are fundamental components of the phospholipids in cell membranes. They are released mainly through the action of phospholipase A2 and then metabolised to signalling molecules known as eicosanoids.46 The partial substitution of omega-3 in place of omega-6 fatty acids favours the synthesis of generally weaker prostanoids (for example, thromboxane A3, which, contrary to omega-6-derived thromboxane A2, has minimal platelet-aggregating and vaso-constrictive potency).47 The results of these changes in eicosanoid production are vasodilatation as well as inhibition of platelet aggregation and inflammation.
The beneficial effects of omega-3 PUFA are brought about not just by the modulation of the amount and types of eicosanoids produced47 but also the regulation of intracellular signalling pathways, transcription factor activity48 and gene expression.49 The combination of these mechanisms result in the regulation of inflammation, platelet adhesion, blood pressure regulation, heart rhythm and triglycerides.50
Omega-3 fatty acids in health
Clinical evidence supports the use of omega-3 fatty acids in a number of inflammatory conditions, including many of the co-morbidities of obesity, such as CVD,39 hypertension,51, 52 T2DM44 and dyslipidemia.53
In 1999, the GISSI-Prevenzione trial recruited 11 324 people with a recent history of MI for treatment with 1 g per day of marine omega-3 fatty acids. During the 3.5 years of supplementation, results showed reduced occurrences of all causes of mortality (20%), cardiovascular death (30%) and sudden cardiac death (45%).38 This is in agreement with other reviews indicating decreased mortality and cardiovascular incidents associated with regular consumption of fish and marine lipid supplements.40, 41
Systemic inflammation, characterised by increased levels of inflammatory markers such as CRP, interleukin (IL)-6 and TNFα, is an indicator for increased risk of CVD.46, 54 Increased circulating levels of these inflammatory markers have been correlated with cardiovascular risk factors, including hypertension and metabolic syndrome.55, 56 Australia’s National Heart Foundation recommendations currently include supplementation with omega-3 fatty acids for decreasing the risk of heart disease, as well as for individuals with documented CVD and elevated triglycerides (up to 4000 mg/day).57 Research continues to identify and explore the novel mechanisms by which omega-3 exerts its benefit in CVD.
Although a review published by Rizos et al.58 found no significant reduction in all-cause mortality or cardiac death associated with omega-3 intake, these results should be interpreted with caution given that the mean does of omega-3 from the 20 studies included was 1.51 g/day and only 10 these studies utilised a dose ⩾1 g/day of omega-3.
Many properties ascribed to omega-3 fatty acids are applicable not just to patients with CVD but also to diabetic patients. These include improved triglycerides,44 anti-inflammatory, antithrombotic and antiatherogenic effects of fish oil.59 Of further interest, a lower prevalence of diabetes60, 61, 62, 63, 64 and glucose intolerance65 have been reported in populations known to have a very high omega-3 fatty acid intake (for example, Greenland, Alaska, Faroe Islands). An inverse correlation between omega-3 intake and conditions such as diabetes and glucose intolerance has been observed in an elderly Dutch population.66 However, a Cochrane review concluded that there is insufficient evidence to demonstrate impaired glycaemic control associated with use of omega-3 in patients with T2DM, showing no statistically significant changes in fasting glucose, fasting insulin or body weight.67 Thus, further clinical and mechanistic studies regarding the effects of omega-3 intake on insulin sensitivity are necessary.
This review aims to explore animal and human data pertaining to the effects of omega-3 fatty acids (marine lipids) on plasma adiponectin and leptin levels, considering plausible mechanisms of action and potential implications for obesity management.
Available studies assessing the effect of omega-3 fatty acids on adiponectin include both human (Table 1) and rodent models.36, 37, 68, 69, 70, 71, 72 Three studies reported significant increases in adiponectin following omega-3 supplementation, one reported non-significant increase and two studies reported minimal changes. Study cohorts varied, including studies of subjects within healthy weight range, as well as those with genetic or dietary-induced obesity. A number of these studies also noted additional benefits following omega-3 fatty acids supplementation. These included reversed diet-induced insulin resistance and dyslipidemia, improved adiposity70 and changes in TNFα.37 Increased adiponectin levels associated with omega-3 fatty acids was demonstrated independently of significant changes in BMI, waist circumference, systolic blood pressure, fasting plasma glucose, total cholesterol, high-density lipoprotein-cholesterol or low-density lipoprotein-cholesterol between the supplemented and control groups.37
In summary, the majority of studies reported omega-3 intake induced statistically significant increases in adiponectin levels in both animal68, 69, 70, 71 and human models.37, 73, 74, 75 These included studies with subjects in normal weight range (18⩽BMI⩽25 kg/m2),73 overweight (25⩽BMI⩽30 kg/m2)74 and obese (BMI⩾30 kg/m2).37, 75 Further, results were consistent between healthy individuals37, 73 and those investigating hyperlipidaemic patients with 2TDM74 or recent history of MI (insignificant increase in adiponectin levels).76
Limited studies were available reporting the effects of omega-3 fatty acids on circulating levels of leptin that included both human (Table 2) and rodent models.36, 68, 69, 77, 78 Of these studies utilising participants with a stable weight (no concurrent weight loss or caloric restriction),36, 68, 69, 76, 79, 80 the majority demonstrated either minimal change or a reduction in leptin levels associated with omega-3.
Perez-Matute et al.69 demonstrated that when introducing a fat-rich hyperenergetic diet with subsequent continuous weight gain in rats, additional supplementation with omega-3 fatty acids resulted in a further increase in leptin levels. In vitro studies demonstrated an EPA-induced increase in leptin mRNA gene expression,77 a result that was less pronounced in the presence of insulin.78 Perez-Matute et al.78 also demonstrated in vitro that EPA-induced increases in leptin secretion were highly correlated with increased glucose utilisation. The study showed an inverse relationship with anaerobic glucose metabolism in both the presence and absence of insulin. Lipogenesis was decreased by EPA in the absence of insulin, whereas lipolysis was unaffected. The authors therefore suggested that EPA, like insulin, stimulates leptin production by increasing the oxidative metabolism of glucose.
There are many inconsistencies within and between the results from human and animal models pertaining to the effects of omega-3 intake on plasma leptin concentrations.68, 69, 76, 79 Insulin resistance and obesity have been posited to lead to inappropriately high plasma leptin levels for a given fat mass.81, 82 Further research indicates that this may occur as a consequence of desensitisation of the leptin signal, a phenomenon referred to as leptin resistance.4 In situations where weight and diet are stable, leptin is thought to signal a set point at which energy intake and energy expenditure are balanced.83 This set point reflects a level of leptin sensitivity, which might vary with genetic, nutritional and/or environmental factors.81
A comparative study between two tribes from Tanzania, with similar BMIs but differing diets, showed that in the tribe who regularly consumed fish (mean BMI 20.4), leptin levels were lower as compared with those in the tribe who did not consume fish regularly (mean BMI 20.1 kg/m2).80 These results were, however, not replicated in a subsequent clinical study.79 These studies differed in study design (comparative population study vs clinical study), sample size (608 vs 35 participants respectively), mean BMI of study population (non-obese vs overweight) and existence of previously established medical conditions (non-specified vs post MI).
Further, data demonstrate that following a weight reduction of 10% in a combination of obese and non-obese subjects, low-dose infusion of leptin (replicating levels before weight reduction) normalises appetite and energy expenditure84 that would otherwise adjust to promote weight regain.85 This observation brings into question the clinical relevance of leptin resistance in relation to weight loss outcomes.
Dosage of omega-3 fatty acids
Of the human studies investigating the effects of omega-3 on these adipokines, the amount of supplementation varied significantly.37, 73, 74, 76, 79, 80, 86, 87 Not all studies specified the amount of marine lipid (mg/day) and/or the amount of omega-3 (EPA/DHA) they contained. In studies where omega-3 fatty acids were derived from dietary sources, Mori et al.79 and Flachs et al.36 reported the addition of a daily fish meal clarifying the average amount of omega-3 but not EPA and DHA. Winnicki et al.80 specified the amount of fish, though not omega-3, EPA or DHA, which makes dose calculations difficult as EPA and DHA content can vary from 177 mg/100 g in catfish through to 2648 mg/100 g in salmon40 and will also vary according to the region from which it is sourced. Of further interest, an additional study in overweight and obese participants, greater decreases were observed in adiponectin levels through supplemented intake of omega-3 by comparison to equivalent increase in dietary intake of omega-3,88 suggesting that differences in results between studies may be related not just to the dose but also the form of omega-3 (dietary or supplemented).
Oral supplementation dosages (where specified) ranged from 1 to 3.6 g per day of Omega-3 PUFA.73, 76, 79, 86, 87 EPA ranged from 465 to 1800 mg/day74, 76 and DHA was only specified in one study with a value of 375 mg/day.76 Study comparisons included either baseline levels of subjects or a control group (no supplement, unspecified placebo or supplementation with alternative lipid source). The majority of studies utilising doses of omega-3 that exceeded 1 g/day were more likely to report significant changes in adipokine levels.37, 73, 74, 79
Implications of increasing adiposity
Increasing adiposity (as approximated by BMI) correlates with decreased plasma adiponectin and increased plasma leptin levels.4 Hence, it is interesting to further consider the effects of omega-3 fatty acids on these adipokines across different BMI groups. Although the available data are limited, it appears that omega-3 fatty acid supplementation further increases adiponectin levels in obese vs lean individuals (Figure 2a).
Data pertaining to omega-3 and leptin are less clear (Figure 2b). This figure illustrates changes in the magnitude of the omega-3 fatty acid-induced changes in plasma leptin levels across different studies. Observations are presented according to BMI. In non-obese subjects, leptin levels decreased following supplementation.80 Conversely, in studies incorporating severely obese subjects, leptin levels increased. There were, however, some inconsistencies within these results, for example, Patel et al.76 inducted subjects who had recently experienced an MI. This may have been associated with alterations in other risk factors for obesity and CVD such as cholesterol. Mean BMI also differed between cohorts (20.1 vs 27.4 kg/m2). The effect of omega-3 fatty acid supplementation in overweight individuals may differ in an overweight but otherwise healthy cohort.
Given the limitations in the available data, further research in this area is warranted, specifically larger-scale trials investigating the effects in both healthy individuals with differing BMI as well as trials investigating the effect of omega-3 PUFA on these adipokines in different pathological conditions.
Limitations in available literature
Adipokines are influenced by dietary fat and energy intakes.89 Thus trials involving placebos that contain other fatty acids can be problematic in this area of research. This was clearly demonstrated by Iariu et al.86 where greater changes in adipokine levels were observed in the control group (supplemented with 20 g butterfat; caloric equivalent to 3.36 g omega-3 supplement in the treatment group) than in those supplemented with omega-3. Other studies included within this review compared omega-3 groups with either standardised diet or the same standardised diet with the inclusion of other lipids. Primary limitations within currently available literature include differences in the method of dose reporting (as previously mentioned, this makes comparison between the trials difficult) and the lack of large-scale, controlled trials with a suitable comparator diet or inactive supplement.
Mitochondrial function in obesity
Adipocytes undergo two stages of development: differentiation and hypertrophy.90 Early stage maturation (differentiation) presents with adipocytes that have a higher level of metabolic activity and fuel consumption. During this stage, cells are relatively small and insulin sensitive and demonstrate increased adiponectin expression. By contrast, cells from aged tissue have increased size (hypertrophy) and have lost most of their functional activities, including adiponectin synthesis.90, 91 In obesity, the number of hypertrophied fat cells also increases,91 with subsequent reduction in the mitochondrial protein content.92 This correlates with data from pharmaceutical therapies known to either increase or decrease mitochondrial protein content and/or function also noted to alter adiponectin levels. For example, the thiazolidinediones class of drugs are known to stimulate adipocyte differentiation and prevent hypertrophy.93 This occurs as a result of increased mitochondrial protein content of adipocytes.92 Further, thiazolidinediones increase adiponectin synthesis.94, 95 Conversely, anti-HIV drugs induce peripheral fat wastage and central adiposity, with the latter characterised by mitochondrial defects96 and hence are associated with reduced adiponectin synthesis.97 As adiponectin synthesis is linked to mitochondrial function in adipocytes,91 it is plausible that the mitochondrial dysfunction associated with obesity98 is a contributing factor in the concurrent decrease observed in adiponectin levels (Figure 3).
Omega-3 fatty acids and inflammation
Omega-3 fatty acids have an integral role in the prevention and treatment of CVD,57 arthritis and other inflammatory or autoimmune disorders.1 Studies specifically assessing anti-inflammatory effects of omega-3 have reported differing results. Pot et al.99 demonstrated no significant changes in inflammatory markers associated with omega-3 intake in healthy individuals. By contrast, other studies have demonstrated an omega-3 fatty acid-induced inhibition of nuclear transcription factor kappa B (NFκB), a key transcription factor in cytokine gene expression, cellular adhesion and inflammation.100, 101, 102 Omega-3 has also been shown to suppress monocyte synthesis of pro-inflammatory mediators, including IL-1,4, 103, 104 IL-6105 and TNFα.103, 106, 107 Due to the correlation between inflammatory markers such as IL-6, BMI and percentage body fat, it has been suggested that these inflammatory markers may have a role in the link between obesity and insulin resistance.108
Esposito et al.109 investigated the effects of weight loss and lifestyle changes on vascular inflammatory markers in obese women. After 2 years, BMI decreased more in the intervention group (weight loss and lifestyle modification) than in control subjects, as did serum concentrations of IL-6, IL-18 and CRP. Adiponectin levels increased significantly in correlation with decreased levels of these inflammatory markers. Omega-3-associated changes in adiponectin have been linked to concurrent changes in pro-inflammatory cytokines, such as TNFα.37 The reverse has also been demonstrated, with TNFα shown to dose-dependently reduce circulating measures of adiponectin.94 Therefore, it is hypothesised that the ability of omega-3 fatty acids to decrease adiponectin, at least in part, may be due to their ability to downregulate TNFα and other inflammatory markers.
Circulating leptin concentrations have been positively correlated with levels of CRP,110 as well as TNFα,111, 112 independently of BMI.113 Leptin and TNFα both increase with weight gain, decrease with weight loss, and are commonly elevated in obesity.111 The elevated expression of TNFα in obesity is thought to be a contributing factor to the subsequent development of hyperleptinemia.114, 115, 116
It is proposed that the decrease in inflammatory cytokines (NFκB, TNFα, IL-1 and IL-6), associated with omega-3 fatty acid supplementation, induces an increase in adipocyte production of adiponectin, along with improved leptin sensitivity and a corresponding decrease in leptin production (Figure 4).
Omega-3 fatty acid supplementation is widely utilised for a variety of medical conditions, including CVD, dyslipidemia, hypertension, T2DM and arthritis. To date, results of studies investigating their impact on obesity development and progression have been inconclusive. By specifically exploring the effects of these fatty acids on adipose hormones in human subjects, a clear dose-dependent inverse correlation is observed between omega-3 intake and adiponectin levels. This is of particular interest given that decreased circulating levels of adiponectin in obesity are associated with increased risk of coronary artery disease and MI whereas increased levels are associated with enhanced insulin sensitivity.
Conversely, the magnitude of omega-3-induced changes in plasma leptin levels appear to be partially dependent on BMI. By summarising available data, omega-3 supplementation appears to decrease plasma leptin levels in non-obese subjects, yet increase levels in severely obese subjects. In non-obese individuals, leptin serves to decrease food intake and increase energy expenditure. In obese subjects, where weight is stable, a resistance to the endogenous effects of leptin develops. These increased levels are also associated with the development of CVD. However, in obese subjects on a calorie-restricted diet, infusion of leptin to replicate levels of leptin observed before weight reduction is able to reverse the expected changes in appetite and energy expenditure that would otherwise promote weight regain. Omega-3-associated increases in leptin levels observed in obese subjects may pose benefits in the prevention of weight regain during calorie-restricted diets in this group.
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LV received funding from FIT Bioceuticals for the scholarship support of BG. These sponsors had no involvement in the collection, analysis or interpretation of the data; writing the report; or the decision to submit the paper for Publication. LV has received National Institute of Complementary Medicine and National Health and Medical Research Council of Australia competitive funding and Industry support for research into nutraceuticals.
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Gray, B., Steyn, F., Davies, P. et al. Omega-3 fatty acids: a review of the effects on adiponectin and leptin and potential implications for obesity management. Eur J Clin Nutr 67, 1234–1242 (2013). https://doi.org/10.1038/ejcn.2013.197
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