Inflammation and the link with obesity
It’s well established that dietary and lifestyle changes can help with the management of obesity. Recent evidence, however, suggests that insulin resistance, as a consequence of obesity and in particular excess accumulation of visceral fat, may be preventable by adopting relatively simple dietary approaches that modulate inflammation.
Eicosapentaenoic acid (EPA) is an omega-3 fatty acid already recognised as a successful dietary intervention for the treatment of inflammation-related health conditions. EPA’s role in reducing whole-body inflammation may also play a role in prevention of the co-morbidities associated with obesity-induced inflammatory insulin resistance. Insulin resistance is the prerequisite to the development of metabolic syndrome, the risk factor for a number of serious and potentially life-threatening diseases, including type II diabetes and cardiovascular disease; prevention is therefore imperative to controlling the negative health consequences arising from insulin resistance. Today, 60% of adults and 30% of children aged between 2 and 15 are overweight or obese; health problems associated with being overweight or obese cost the NHS more than £5 billion every year.
The impact of our carbohydrate choices
Increased availability of energy-dense, nutrient-poor food that is rich in saturated fat and high in added sugar, coupled with sedentary lifestyles creates the ticking time bomb for obesity-driven poor health. Overloading the body with simple carbohydrates is known to be detrimental to health and many of the high-carbohydrate foods common to Western diets produce a high glycaemic response that leads over time to obesity, insulin resistance, metabolic syndrome and type II diabetes. The direct link between inflammation and insulin resistance, related to obesity, offers an alternative and simple approach to reducing the potentially devastating impact that obesity has on our health.
Insulin is anti-inflammatory and glucose is inflammatory
Insulin is generally considered to be an anti-inflammatory hormone whilst the effects of glucose are known to be proinflammatory.  Glucose, whilst a critical substrate for energy production, has adverse effects when levels are either too low or too high. Insulin is a hormone with many diverse functions; these include stimulation of glucose transport into cells, regulation of gene expression, modification of enzyme activity and regulation of energy homeostasis. For example, in skeletal muscle, insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter to the plasma membrane, whilst in the liver, insulin inhibits the expression of key gluconeogenic enzymes. Insulin signalling is via a complex signalling cascade that starts with binding of the insulin receptor. An increase in pro-inflammatory cytokine release as a result of a high glucose status can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. A carbohydrate-dense meal increases glucose levels, thereby stimulating the production of tumour necrosis factor alpha (TNFα), a pro-inflammatory cytokine secreted predominantly by monocytes and macrophages. Activation of the TNF receptor then results in stimulation of the pro-inflammatory transcription factor nuclear factor kappaB (NFκB). NFκB is normally found bound to an inhibitor protein, which acts to restrict its movement within the cell cytoplasm. Stimulation of cells by TNFα (or other pro-inflammatory cytokines) stimulates the release of NFκB from the inhibitor protein, enabling it to move into the nucleus where it then stimulates further transcription of pro-inflammatory cytokines (such as TNFα, IL-1, and IL-6) that impair normal insulin signalling pathways. As type II diabetes starts to develop, the body becomes less sensitive to insulin and the resulting insulin resistance leads to further inflammation, resulting in a vicious cycle of inflammation causing more insulin resistance, and therefore higher blood glucose which in turn increases inflammation. High glucose levels also induce oxidative stress and inflammatory changes, with chronic low-grade inflammation a common observation in insulin-resistant individuals.
It’s not just fat: understanding adipose tissue
Whilst we generally think of fat (adipose) simply as a tissue that is dedicated solely to energy storage, adipose tissue is a complex mixture of adipocytes, pre-adipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells including mast cells, eosinophils, B cells, T-cells and macrophages. Macrophages function to remove dying or dead cells or cellular debris, and the presence of dead adipocytes is, itself, a hallmark of obesity, whilst the numbers of macrophages strongly correlates with bodyweight, body mass index and total body fat. Obesity can also induce a phenotypic switch in these cells towards an M1 phenotype that is highly inflammatory in nature when compared to the anti-inflammatory M2-macrophages. The production of inflammatory cytokines such as tumour necrosis factor-α (TNFα) is mostly derived from M1 macrophages rather than adipocytes themselves. Adipose tissue should therefore be considered as an immunologically active organ displaying hallmarks of both an innate and adaptive immune response, with both the quantity and the nature of immune cell subtypes produced being influenced by obesity.
Adipose tissue growth is via both an increase in size and number of adipocytes, with calorie excess resulting in both. This then leads to cellular stress that in turn initiates oxidative stress and an inflammatory response within adipose tissue. Whilst the function of adipose tissue is to produce hormones that regulate feeding behaviour (such as leptin and adiponectin), it also generates pro- and anti-inflammatory adipokines (fat-derived cytokines); the inflammatory responses in adipose tissues can thus become self-stimulating leading to increased local and systemic levels of various pro-inflammatory cytokines (including TNFα, IL-6 and IL-1β) that have the potential to induce insulin resistance. Obesity-related hyperlipidaemia, hyperglycaemia and oxidative stress, can also induce insulin resistance in peripheral tissues and can induce activation of inflammatory signaling cascades in adipose tissues that then further contribute to inflammatory adipokine production. It stands to reason, therefore, that agents that can reduce or block the pathways of adipokine production have huge potential as interventions for the prevention of inflammatory-mediated insulin resistance.
The AA to EPA ratio, inflammation and insulin resistance
The overconsumption of omega-6 polyunsaturated fatty acids, resulting in a high ratio of omega-6 to omega-3, contributes to the increased pathogenesis of obesity by promoting low-grade chronic inflammation. [4, 5] More specifically, a high ratio of the key fatty acids omega-6 arachidonic acid to omega-3 eicosapentaenoic acid (AA to EPA) is a biomarker of inflammation: AA is the precursor of products with a significant pro-inflammatory nature, whilst those derived from EPA are anti-inflammatory. A high AA to EPA ratio is associated with obesity, insulin resistance and metabolic syndrome. [6, 7] Lowering the AA to EPA ratio through dietary modification and EPA intervention is a potential mechanism for reducing the prevalence of the metabolic syndrome by preventing inflammatory driven insulin resistance.
EPA reduces insulin resistance by modulating inflammation
As a source of the long-chain omega-3 fatty acids EPA and docosahexaenoic acid (DHA), well documented for their anti-inflammatory effects, fish oils have the potential to ameliorate adipose tissue inflammation in subjects with obesity and insulin resistance.  In vitro and animal studies demonstrate that fish oil consumption increases the levels of EPA and DHA in adipocytes, protects adipose tissue against inflammation and insulin resistance,  reduces adipose tissue macrophages and alters the inflammatory phenotype of the remaining macrophages. EPA has been shown in vitro to suppress TNFα activity by preventing NFκB activation  thereby preventing the further transcription of pro-inflammatory cytokines known to impair normal insulin signalling pathways. Adiponectin secreted by adipose tissue is a marker for insulin sensitivity, with higher circulating levels associated with a lower risk of type II diabetes. Meta-analysis shows that intake of fish oil increases blood levels of adiponectin, supporting the benefits of fish oil consumption for glucose control and fat cell metabolism.  Unsurprisingly, in addition to decreasing the AA to EPA ratio and secretion of proinflammatory adipokines, EPA’s ability to protect against the development of insulin resistance is thought to be through the increased secretion of adiponectin. [12, 13]
Let’s get supplementing
The inflammatory response triggered by obesity involves many components of the classical inflammatory response to pathogens, with a corresponding rise in circulating inflammatory end products. Current recommendations for counteracting obesity as a measure for reducing the risk of developing insulin resistance, and subsequent health issues, advocate the consumption of a healthy diet and participation in regular physical activity, but many individuals have difficulty complying with these recommendations. EPA treatment has been shown to prevent and reverse insulin resistance, in part through interference with the AA cascade that produces proinflammatory eicosanoids, the formation of novel bioactive lipid mediators, and direct changes in the pattern of adipocytokine secretions. In addition to these benefits, EPA elicits a number of effects which might be useful for reducing obesity, including suppression of appetite and changes in gene expression which shift metabolism towards increased accretion of lean tissue, enhanced fat oxidation and energy expenditure, and reduced fat deposition. 
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- Liu HQ, Qiu Y, Mu Y, Zhang XJ, Liu L, Hou XH, Zhang L, Xu XN, Ji AL, Cao R, et al: A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity-linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats. Nutrition research 2013, 33:849-858.
- Inoue K, Kishida K, Hirata A, Funahashi T, Shimomura I: Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity. Nutr Metab (Lond) 2013, 10:25.
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- Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, Shipp LR, Lee J, Walton RG, Adu A, Erfani R, et al: Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes 2013, 62:1709-1717.
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- Zhao Y, Joshi-Barve S, Barve S, Chen LH: Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr 2004, 23:71-78.
- Wu JH, Cahill LE, Mozaffarian D: Effect of fish oil on circulating adiponectin: a systematic review and meta-analysis of randomized controlled trials. The Journal of clinical endocrinology and metabolism 2013, 98:2451-2459.
- Kalupahana NS, Claycombe K, Newman SJ, Stewart T, Siriwardhana N, Matthan N, Lichtenstein AH, Moustaid-Moussa N: Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation. J Nutr 2010, 140:1915-1922.
- Ito R, Satoh-Asahara N, Yamakage H, Sasaki Y, Odori S, Kono S, Wada H, Suganami T, Ogawa Y, Hasegawa K, Shimatsu A: An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with Dyslipidemia. J Atheroscler Thromb 2014, 21:248-260.
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