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.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K . Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784–1792.
Zhang F, Basinski M, Beals J, Briggs S, Churgay L, Clawson D et al. Human obesity protein, leptin. RCSB Protein Data Bank. Nature 1997; 387: 206–209.
Krauss R, Eckel R, Howard B, Appel L, Daniels S, Deckelbaum R et al. AHA Dietary Guidelines Revision 2000: a statement for healthcare professionals from the nutrition committee of the American Heart Association. Circulation 2000; 102: 2284–2299.
Meier U, Gressner A . Endocrine Regulation of Energy Metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin and resistin. Clin Chem 2004; 50: 1511–1525.
Knudson J, Dick G, Tune J . Adipokines and coronary vasomotor dysfunction. Exp Biol Med 2007; 232: 727–736.
Cavusoglu E, Ruwende C, Chopra V, Yanamadala S, Eng C, Clark LT et al. Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain. Eur Heart J 2006; 27: 2300–2309.
Kaidar-Person O, Person B, Szomstein S, Rosenthal R . Nutritional deficiencies in morbidly obese patients: a new form of malnutrition? Part A: Vitamins. Obes Surg 2008; 18: 870–876.
Ren J . Leptin and hyperleptinemia—from friend to foe for cardiovascular function. J Endocrinol 2004; 181: 1–10.
Sattar N, Wannamethee G, Sarwar N, Tchernova J, Cherry L, Wallace A et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation 2006; 114: 623–629.
Civitarese A, Ukropcova B, Carling S, Hulver M, DeFronzo R, Mandarino L et al. Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 2006; 4: 75–87.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731–737.
Dekker J, Funahashi T, Nijpels G, Pilz S, Stehouwer C, Snijder M et al. Prognostic value of adiponectin for cardiovascular disease and mortality. J Clin Endocrinol Metab 2008; 93: 1489–1496.
Nakamura Y, Shimada K, Fukuda D, Shimada Y, Ehara S, Hirose M et al. Implications of plasma concentrations of adiponectin in patients with coronary artery disease. Heart 2004; 90: 528–533.
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB . Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730–1737.
Considine R, Sinha V, Heiman M, Kriauciunas A, Stephens T, Nyce M et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292–295.
Frederich R, Hamann A, Anderson S, Lollmann V, Lowell B, Flier J . Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1: 1311–1314.
Skurk T, Alberti-Huber C, Herder C, Hauner H . Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023–1033.
Houseknecht K, Baile C, Matteri R, Spurlock M . The biology of leptin: a review. J Anim Sci 1998; 76: 1405–1420.
Auwerx J, Staels B . Leptin. Lancet 1998; 351: 737–742.
Jequier E . Leptin signaling, adiposity, and energy balance. Ann NY Acad Sci 2002; 967: 379–388.
Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL . Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab 1997; 82: 561–565.
Cameron AJ, Welborn TA, Zimmet PZ, Dunstan DW, Owen N, Salmon J et al. Overweight and obesity in Australia: the 1999–2000 Australian Diabetes, Obesity and Lifestyle Study (AusDiab). MJA 2003; 178: 427–432.
Madsen E, Bruun J, Skogstrand K, Hougaard D, Christiansen T, Richelsen B . Long-term weight loss decreases the nontraditional cardiovascular risk factors interleukin-18 and matrix metalloproteinase-9 in obese subjects. Metabolism 2009; 58: 946–953.
Jequier E . Obesity. Impairment of energy intake or of energy expenditure. Ann Endocrinol (Paris) 1995; 56: 87–92.
Legradi G, Emerson CH, Ahima RS, Flier JS, Lechan RM . Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997; 138: 2569–2576.
Friedman J, Halass J . Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763–777.
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ et al. Leptin regulates proinflammatory immune responses. FASEB J 1998; 12: 57–65.
Shamsuzzaman AS, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 2004; 109: 2181–2185.
Corsonello A, Perticone F, Malara A, De Domenico D, Loddo S, Buemi M et al. Leptin-dependent platelet aggregation in healthy, overweight and obese subjects. Int J Obes Relat Metab Disord 2003; 27: 566–573.
Konstantinides S, Schafer K, Loskutoff DJ . The prothrombotic effects of leptin possible implications for the risk of cardiovascular disease in obesity. Ann NY Acad Sci 2001; 947: 134–141. discussion 41–2.
Rolls B, Drewnowski A, Ledikwe J . Changing the energy density of the diet as a strategy for weight management. J Am Diet Assoc 2005; 105: S98–S103.
Moussavi N, Gavino V, Receveur O . Could the quality of dietary fat, and not just its quantity, be related to risk of obesity? Obesity 2008; 16: 7–15.
Duncan K, Bacon I, Weinsier R . The effects of high and low energy density diets on satiety, energy intake, and eating time of obese and nonobese subjects. Am J Clin Nutr 1983; 37: 763–767.
Johansson L, Solvoll K, Bjorneboe G, Drevon C . Under- and overreporting of energy intake related to weight status and lifestyle in a nationwide sample. Am J Clin Nutr 1998; 68: 266–274.
Micallef M, Munro I, Phang M, Garg M . Plasma n-3 polyunsaturated fatty acids are negatively associated with obesity. Brit J Nutr 2009; 102: 1370–1374.
Flachs P, Mohamed-Ali V, Horakova O, Rossmeisl M, Hosseinzadeh-Attar M, Hensler M et al. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Diabetologia 2006; 49: 394–397.
Itoh M, Suganami T, Satoh N, Tanimoto-Koyama K, Yuan X, Tanaka M et al. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. Am Heart Assoc J 2007; 27: 1918–1925.
Marchioli R, Valagussa F . The results of the GISSI-Prevenzione trial in the general framework of secondary prevention. Eur Heart J 2000; 21: 949–952.
Ruxton C, Reed S, Simpson M, Millington K . The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence. J Hum Nutr Diet 2004; 17: 449–459.
Mozaffarian D, Rimm EB . Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 2006; 296: 1885–1899.
Wang Z, Al-Regaiey KA, Masternak MM, Bartke A . Adipocytokines and lipid levels in Ames dwarf and calorie-restricted mice. J Ferontol Ser A Biol Sci Med Sci 2006; 61A: 323–331.
Nahin R, Barnes P, Stussman B, Bloom B . Costs of Complementary and Alternative Medicine (CAM) and Frequency of Visits to CAM Practitioners: United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention: Hyattsville, USA, 2009.
National Institutes of Health. Get the Facts: Omega-3 Supplements: An Introduction. Department of Health and Human Services: Bethesda, MD, USA, 2012.
Mori T, Bao D, Burke V, Puddey I, Watts G, Beilin L . Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr 1999; 70: 817–825.
Simopoulos A . Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70 (suppl), S560–S569.
Simopoulos A . Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002; 21: 495–505.
Serhan C, Arita M, Hong S, Gotlinger K . Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirintriggered epimers. Lipids 2004; 39: 1125–1132.
Babcock T, Kurland A, Helton W, Rahman A, Anwar K, Espat N . Inhibition of activator protein-1 transcription factor activation by omega-3 fatty acid modulation of mitogen-activated protein kinase signaling kinases. Parenter Enteral Nutr 2003; 27: 176–180.
Ren B, Thelen A, Peters J, Gonzalez F, Jump D . Polyunsaturated fatty acid suppression of hepatic fatty acid. Synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha. J Biol Chem 1997; 272: 26827–26832.
Harris W, Miller M, Tighe A, Davidson M, Schaefer E . Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008; 197: 12–24.
Morris M, Sacks F, Rosnerm B . Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation 1993; 88: 523–533.
Appel L, Miller E, Seidler A, Whelton P . Does supplementation of diet with ‘fish oil’ reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med 1993; 153: 1429–1438.
Harris W . n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997; 65: 1645–54S.
Hansson G . Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
Hotamisligil G, Arner P, Caro J, Atkinson R, Spiegelman B . Increased adipose tissue expression of tumor necrosis factor-a in human obesity and insulin resistance. J Clin Invest 1995; 95: 2409–2415.
Kressel G, Trunz B, Bub A, Hülsmann O, Wolters M, Lichtinghagen R et al. Systemic and vascular markers of inflammation in relation to metabolic syndrome and insulin resistance in adults with elevated atherosclerosis risk. Atherosclerosis 2009; 202: 263–271.
Heart Foundation Australia. Fish, fish oils, n-3 polyunsaturated fatty acids and cardiovascular health. Heart Foundation Australia 2008, [cited 25 May 2010]; Available from http://www.heartfoundation.org.au/SiteCollectionDocuments/HW_FS_FishOils_PS_FINAL_web.pdf.
Rizos E, Ntzani E, Bika E, Kostapanos M, Elisaf M . Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012; 308: 1024–1033.
Holub B . Clinical nutrition: omega-3 fatty acids in cardiovascular care. CMAJ 2002; 166: 608–615.
Jorgensen M, Bjeregaard P, Borch- Johnsen K . Diabetes and impaired glucose tolerance among the Inuit population of Greenland. Diabetes Care 2002; 25: 1766–1771.
Mouratoff G, Scott E . Diabetes mellitus in Eskimos after a decade. JAMA 1973; 226: 1345–1346.
Young T, Schraer C, Shubnikoff E, Szathmary E, Nikitin Y . Prevalence of diagnosed diabetes in circumpolar indigenous populations. Int J Epidemiol 1992; 21: 730–736.
Burrows N, Geiss L, Engelgau M, Acton K . Prevalence of diabetes among Native Americans and Alaska Natives, 1990–1997: an increasing burden. Diabetes Care 2000; 23: 1786–1790.
Simonsen T, Vartun A, Lyngmo V, Nordoy A . Coronary heart disease, serum lipids, platelets and dietary fish in two communities in northern Norway. Acta Med Scand 1987; 222: 237–245.
Adler A, Boyko E, Schraer C, Murphy N . Lower prevalence of impaired glucose tolerance and diabetes associated with daily seal oil or salmon consumption among Alaska Natives. Diab Care 1994; 17: 1498–1501.
Feskens E, Virtanen S, Rasanen L, Tuomilehto J, Stengard J, Pekkanen J et al. Dietary factors determining diabetes and impaired glucose tolerance: a 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study. Diab Care 1995; 18: 1104–1112.
Hartweg J, Perera R, Montori V, Dinneen S, Neil A, Farmer A . Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus (Review). Cochrane Database Syst Rev 2008; 1: 1–60.
Neschen S, Morino K, Rossbacher J, Pongratz R, Cline G, Sono S et al. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes 2006; 55: 924–928.
Pérez-Matute P, Pérez-Echarri N, Martínez J, Marti A, Moreno-Aliaga M . Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-α. Br J Nutr 2007; 97: 389–398.
Rossi AS, Lombardo YB, Lacorte JM, Chicco AG, Rouault C, Slama G et al. Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol 2005; 289: R486–R494.
Burghardt P, Kemmerer E, Buck B, Osetek A, Yan C, Koch L et al. Dietary n-3:n-6 fatty acid ratios differentially influence hormonal signature in a rodent model of metabolic syndrome relative to healthy controls. Nutr Metab 2010; 7: 1–6.
Buettner R, Scholmerich J, Bollheimer L . High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity 2007; 15: 798–808.
Kondo K, Morino K, Nishio Y, Kondo M, Fuke T, Ugi S et al. Effects of a fish-based diet on the serum adiponectin concentration in young, non-obese, healthy Japanese subjects. J Atheroscler Thromb 2010; 17: 628–637.
Nomura S, Shouzu A, Omoto S, Inami N, Ueba T, Urase F et al. Effects of eicosapentaenoic acid on endothelial cell-derived microparticles, angiopoietins and adiponectin in patients with type 2 diabetes. J Atheroscler Thromb 2009; 16: 83–90.
Gammelmark A, Madsen T, Varming K, Lundbye-Christensen S, Schmidt E . Low-dose fish oil supplementation increases serum adiponectin without affecting inflammatory markers in overweight subjects. Nutr Res 2012; 32: 15–23.
Patel JV, Lee KW, Tomson J, Dubb K, Hughes EA, Lip GY . Effects of omega-3 polyunsaturated fatty acids on metabolically active hormones in patients post-myocardial infarction. Int J Cardiol 2007; 115: 42–45.
Murata M, Kaji H, Takahashi Y, Iida K, Mizuno I, Okimura Y et al. Stimulation by eicosapentaenoic acids of leptin mRNA expression and its secretion in mouse 3T3-L1 adipocytes in vitro. Biochem Biophys Res Commun 2000; 270: 343–348.
Perez-Matute P, Marti A, Martinez JA, Fernandez-Otero MP, Stanhope KL, Havel PJ et al. Eicosapentaenoic fatty acid increases leptin secretion from primary cultured rat adipocytes: Role of glucose metabolism. Am J Physiol Regul Integr Comp Physiol 2005; 288: R1682–R1688.
Mori TA, Burke V, Puddey IB, Shaw JE, Beilin LJ . Effect of fish diets and weight loss on serum leptin concentration in overweight, treated-hypertensive subjects. J Hypertens 2004; 22: 1983–1990.
Winnicki M, Somers VK, Accurso V, Phillips BG, Puato M, Palatini P et al. Fish-rich diet, leptin, and body mass. Circulation 2002; 106: 289–291.
Peyron-Caso E, Taverna M, Guerre-Millo Ml, se AVr, Pacher N, Slama Gr et al. Dietary (n-3) polyunsaturated fatty acids up-regulate plasma leptin in insulin-resistant rats. J Nutr 2002; 132: 2235–2240.
Rosicka M, Krsek M, Matoulek M, Jarkovska Z, Marek J, Justova V et al. Serum ghrelin levels in obese patients: the relationship to serum leptin levels and soluble leptin receptors levels. Physiol Res 2003; 52: 61–66.
Greenberg JA, Boozer CN . The leptin-fat ratio is constant, and leptin may be part of two feedback mechanisms for maintaining the body fat set point in non-obese male Fischer 344 rats. Horm Metab Res 1999; 31: 525–532.
Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest 2005; 115: 3579–3586.
Ahima R, Kelly J, Elmquist J, Flier J . Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology 1999; 140: 4923–4931.
Itariu B, Zeyda M, Hochbrugger E, Neuhofer A, Prager G, Schindler K et al. Long-chain n−3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am J Clin Nutr 2012; 96: 1137–1149.
Koh K, Quon M, Shin K, Lim S, Lee Y, Sakuma I et al. Significant differential effects of omega-3 fatty acids and fenofibrate in patients with hypertriglyceridemia. Atherosclerosis 2012; 220: 537–544.
Neale E, Muhlhausler B, Probst Y, Batterham M, Fernandez F, Tapsell L . Short-term effects of fish and fish oil consumption on total and high molecular weight adiponectin levels in overweight and obese adults. Metabolism 2013; 62: 651–660.
Yannakoulia M, Yiannakouris N, Blüher S, Matalas A, Klimis-Zacas D, Mantzoros C . Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrino Metab 2003; 88: 1730–1736.
Yu Y, Zhu H . Chronological changes in metabolism and functions of cultured adipocytes: a hypothesis for cell aging in mature adipocytes. Am J Physiol Endocrinol Metab 2004; 286: E402–E410.
Koh E, Park J, Park H, Jeon M, Ryu J, Kim M et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 2007; 56: 2973–2981.
Choo H, Kim J, Kwon O, Lee C, Mun J, Han S et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 2006; 49: 784–791.
Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276: 41245–41254.
Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50: 2094–2099.
Karbowska J, Kochan Z . Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPARg. Biochem Pharmacol 2005; 70: 249–257.
van Vonderen M, van Agtmael M, Hassink E, Milinkovic A, Brinkman K, Geerlings S et al. Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss. PLoS One 2009; 4: e5647.
Addy C, Gavrila A, Tsiodras S, Brodovicz K, Karchmer A, Mantzoros C . Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrino Metab 2003; 88: 627–636.
Ferranti Sd, Mozaffarian D . The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54: 945–955.
Pot G, Brouwer I, Enneman A, Rijkers G, Kampman E, Geelen A . No effect of fish oil supplementation on serum inflammatory markers and their interrelationships: a randomized controlled trial in healthy, middle-aged individuals. Eu J Clin Nutr 2009; 63: 1353–1359.
Lo C-J, Chiu KC, Fu M, Lo R, Helton S . Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NFkB activity. J Surg Res 1999; 82: 216–221.
Ohata T, Fukuda K, Takahashi M, Sugimura T, Wakabayashi K . Suppression of nitric oxide production in lipopolysaccharide-stimulated macrophage cells by omega 3 polyunsaturated fatty acids. Jpn J Cancer Res 1997; 88: 234–237.
Khair-El-Din T, Sicher S, Vazquez M, Chung G, Stallworth K, Kitamura K et al. Transcription of the murine iNOS gene is inhibited by docosahexaenoic acid, a major constituent of fetal and neonatal sera as well as fish oils. J Exp Med 1996; 183: 1241–1246.
Endres S, Ghorbani R, Kelley V, Georgilis K, Lonnemann G, van der Meer J et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320: 265–271.
Kremer J, Lawrence D, Jubiz W, Di Giacomo R, Rynes R, Bartholomew L et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. clinical and immunological effects. Arthritis Rheum 1990; 33: 810–820.
Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y . Docosahexaenoic and eisosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol 1997; 400B: 589–597.
Endres S . n-3 Polyunsaturated fatty acids and human cytokine synthesis. Lipids 1996; 31: S239–S242.
Meydani S, Endres S, Woods M, Goldin B, Soo C, Morrill L et al. Oral n-3 fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison in young and older women. J Nutr 1991; 121: 547–555.
Yudkin J, Stehouwer C, Emeis J, Coppack S . C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19: 972–978.
Esposito K, Pontillo A, DiPalo C, Giugliano G, Masella M, Marfella R et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003; 289: 1799–1804.
Gnacińska M, Małgorzewicz S, Guzek M, Lysiak-Szydłowska W, Sworczak K . Adipose tissue activity in relation to overweight or obesity. Endokrynol Pol 2010; 61: 160–168.
Corica F, Allegra A, Corsonello A, Buemi M, Calapai G, Ruello A et al. Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects. Int J Obes (Lond) 1999; 23: 355–360.
Dedoussis G, Kapiri A, Samara A, Dimitriadis D, Lambert D, Pfister M et al. Expression of inflammatory molecules and associations with BMI in children. Eur J Clin Invest 2010; 40: 388–392.
van Dielen F, van’t Veer C, Schols A, Soeters P, Buurman W, Greve J . Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obesity 2001; 25: 1759–1766.
Zhang H, Kumar S, Barnett A, Eggo M . Tumor necrosis factor-a exerts dual effects on human adipose leptin synthesis and release. Mol Cell Endocrinol 1999; 159: 79–88.
Kern P, Saghizadeh M, Ong J, Bosch RJ, Deem R, Simsolo RB . The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss and relationship to lipoprotein lipasa. J Clin Invest 1995; 95: 2111–2119.
Kirchgessen T, Uysal K, Wiesbrock S, Marino M, Hotamisligil G . Tumor necrosis factor-alpha contributes to obesityrelated hyperleptinemia by regulation leptin release from adipocytes. J Clin Invest 1997; 100: 2777–2782.
Schmidt E . Marine n-3 fatty acids and thrombosis. Thromb Res 2003; 111: 9–10.
Tomas E, Tsao T, Saha A, Murrey H, Zhang C, Itani S et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 2002; 99: 16309–16313.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003; 423: 762–769.
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.
About this article
Cite this article
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) doi:10.1038/ejcn.2013.197
Effects of a dietary intervention with Mediterranean and vegetarian diets on hormones that influence energy balance: results from the CARDIVEG study
International Journal of Food Sciences and Nutrition (2019)
Effect of omega-3 fatty acids supplementation combined with lifestyle intervention on adipokines and biomarkers of endothelial dysfunction in obese adolescents with hypertriglyceridemia
The Journal of Nutritional Biochemistry (2019)
Supercritical CO2 extraction of lyophilized Açaí (Euterpe oleracea Mart.) pulp oil from three municipalities in the state of Pará, Brazil
Journal of CO2 Utilization (2019)
Impact of fatty acids unsaturation on stability and intestinal lipolysis of bioactive lipid droplets
Colloids and Surfaces A: Physicochemical and Engineering Aspects (2019)
Neuroscience Letters (2019)