In the year 2016-2017 almost 620,000 people were admitted to hospital in the UK with a health problem associated with obesity (1). Being obese increases the likelihood that a person will develop any one of a number of serious diseases including cardiovascular disease (CVD), which is the cause of 26% of all deaths in the UK (2), non-alcoholic fatty liver disease (NAFLD), which is the most common liver problem in the UK and affects 20-30% of the population (3,4), and type-2 diabetes, of which 90% of those diagnosed are overweight or obese (5).
Scientists have discovered that one underlying factor in the development of these conditions is obesity-associated metabolic inflammation.
What is inflammation?
The most studied type of inflammation results from injury or allergy and is seen in physical symptoms we can identify as swelling, heat, redness, pain, and loss of function (6). The biological processes that result in these symptoms involve the production and release of signals at the site of inflammation. These signals can act directly at the site of inflammation as well as being released into the bloodstream to travel to other parts of the body (6).
These signals are produced in response to an inflammatory stimulus and can act to enlarge blood vessels, recruit cells from the blood to the site of inflammation triggering an immune response, promote release of even more inflammation promoting signals, and cause structural changes at the site of inflammation (7, 8).
In cases of a ‘classic’ acute (or short-lived) inflammatory response to a stimulus such as injury or allergy, inflammation occurs quickly and is often resolved by the body without intervention. Although often unpleasant, in this case, it is a healing process. Inflammation associated with obesity, however, differs in that it is a state of low level inflammation that occurs over a longer period of time and is not resolved; this is described as low-grade chronic inflammation (7, 8).
Can our diet influence inflammation?
The cascade of events resulting in inflammation can be triggered by, and respond to, the oversupply of specific components of our diet such as carbohydrate and fat intake. Response to excess dietary fat and carbohydrate plays a major role in glucose and insulin signalling and therefore the progression of insulin resistance and type 2 diabetes which is part of the inflammation seen in severe obesity (7).
Fats also play a role regulating metabolic, immune, and inflammatory processes (8, 9, 10, 11). Not only can our bodies process the dietary fats we consume to use as fuel, and to provide fatty acids for cell membranes, we can also use dietary fatty acids to produce lipid signals which are involved in regulating normal cell function and inflammation (8, 9, 10, 11).
Dietary fats, and signals produced from dietary fats, can trigger inflammation by binding to inflammatory receptors in our bodies. Typically, our diet (a western diet) is higher in saturated and omega-6 fats, than anti-inflammatory omega-3 fats (12, 13). Saturated fats, as well as signals produced from these fats, can interact and activate inflammatory receptors in our body to promote inflammation (14). Omega-6 and omega-3 fatty acids can also regulate inflammation through the production of such signals. The most commonly consumed omega-6 fatty acid is linoleic acid which is largely found in vegetable oils such as safflower and sunflower oils used in western cooking (10, 11, 12, 13). Linoleic acid itself can be used to make lipid signals and can be further metabolised in our bodies to produce arachidonic acid which can be used to make signals that promote inflammations (8, 10, 11). Many signals that are produced from omega-6 fatty acids promote inflammation; however, many of these ‘pro-inflammatory’ signals are required for the proper function of many processes including adipose tissue expansion in response to increased dietary energy intake. Therefore, it is important to mention that omega-6 fatty acids are essential, meaning we need to obtain these from our diet, and are required for human health to maintain homeostasis (balance) in which pro- and anti-inflammatory signalling is controlled to promote normal cell/tissue function.
In contrast, signals produced from omega-3 fatty acids have anti-inflammatory actions meaning they can reduce inflammation (8, 9, 10, 11). Signals derived from both omega-3 and omega-6 fatty acids can also control the expression of genes involved in fat metabolism and inflammatory signal production (8, 9, 10, 11). Dysregulation, or loss of balance, in inflammatory signals results in a pro-inflammatory environment, which is what we see in obesity. When there is increased dietary energy intake beyond our needs, excess energy can be stored as fat in our adipose (fat) tissue. As the adipose tissue mass increases in obesity, the production of chemical signals is triggered (8, 15). Therefore, the amount of, and the type of fats that are stored in the fat tissue (saturated/mono-unsaturated (MUFA)/omega-3/omega-6) can influence the amount, as well as the inflammatory state, of chemical signals produced.
What is adipose tissue?
Adipose tissue is our body’s main store of fat; visceral adipose tissue accumulates around our internal organs, whereas subcutaneous adipose tissue is located directly under the skin. It is this subcutaneous fat which is the body’s main storage pool and is the most recognisably increased in obesity (16). When the storage capacity of the subcutaneous adipose tissue is compromised, such as in obesity, fat can no longer be safely stored and accumulates in the blood and other organs such as the liver. The accumulation of fat in and around our organs (i.e.visceral fat) increases our risk of developing disease. The adipose tissue has a major role in maintaining energy balance; when there is increased energy intake beyond our needs, excess fat is stored inside fat cells known as adipocytes, and in situations where dietary intake is below our needs, lipid can be released from fat cells and back into the bloodstream to be used for energy (15, 16).
The adipose tissue is able to expand to store excess fat; this involves existing fat cells increasing in size, the formation of new fat cells, and the remodelling of the existing tissue to ensure there is adequate blood and oxygen supply to the enlarging area (13, 14). This is part of normal adipose function and is co-ordinated by a balance of both pro- and anti-inflammatory signals, including signals made from the fats stored within the tissue itself (8, 15, 16, 17).
How does adipose tissue inflammation affect the development of metabolic disease?
In ‘normal/healthy’ conditions, the adipose tissue can respond to dietary fat, glucose, and insulin, as well as increased energy intake. This results in increased storage of fat and the enlargement of the tissue as described above, which is part of normal adipose function (8, 15, 16, 17). If there is continued excess energy intake beyond our needs, subsequently causing fat accumulation in the adipose tissue, the tissue becomes overwhelmed and releases pro-inflammatory signals.
The local environment surrounding fat cells restricts how much they can enlarge and without enough oxygen cells die and release pro-inflammatory stress signals. Such signals promote enlargement of blood vessels and movement of immune cells into the tissue to help clear up dying cells and excess lipid. These immune cells can also send out pro-inflammatory signals resulting in a state of chronic low grade inflammation (occurring continually over a long period of time without being resolved) within the adipose tissue (8, 9, 15, 16, 17). This is observed in obesity, especially in cases of severe obesity, and this continued inflammatory state results in loss of normal adipose function. In this scenario, stored fat within the adipose tissue is broken down and released back into the bloodstream where it may accumulate in arteries, contributing to the development of atherosclerosis (plaque in the arteries), high blood pressure, and CVD, and in other organs such as the liver,in which can lead to NAFLD. The adipose tissue can no longer take up large amounts of excess fat, is unresponsive to changes in glucose, and a state of is insulin resistance occurs not only in the adipose tissue but also in muscle and the liver, something commonly seen in the development of type 2 diabetes (15).
‘Anti-inflammatory’ fats
Omega-3 fatty acids have long been investigated for their anti-inflammatory benefits. To read more on the benefits omega-3 fatty acids pose to human health, check out Maeve Hanan’s blog ‘The lowdown on Omega-3’ in the nutrition section of the educational hub.
Measuring levels of omega-3 fatty acids in human blood plasma reflects omega-3 consumption within the last few hours/days. Measuring these in blood cells reflects omega-3 intake over the previous 8-12 weeks, and measuring omega-3 in the adipose tissue is reflective of long term intake up to 1.5/2 years (18). Omega-3 fatty acids incorporated into the adipose tissue can be used to produce lipid signals that can help reduce and resolve inflammation (8, 10, 11, 19).
Actions of omega-3 in adipose tissue
The omega 3 fatty acids; Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to decrease the production of pro-inflammatory signals and increase the production of anti-inflammatory signals (8, 19, 18). In addition to this, EPA and DHA can affect the expression of genes that control cell growth and death, metabolism, environment remodelling, and the further production/release of inflammatory signals (10, 11). Through these mechanisms, EPA and DHA have been seen to control the production and breakdown of fat, promote the formation of new fat cells, decrease the number of pro-inflammatory immune cells, and improve responses to glucose and insulin (8, 10, 11, 20). Signals produced specifically from EPA and DHA have strong anti-inflammatory actions and have been shown to reduce immune cell recruitment and oxidative stress (in which reactive oxygen species cause cell damage) in adipose tissue (19, 20).
However, it has been shown that the amount of plasma omega-3 and changes in insulin sensitivity in response to EPA + DHA supplementation are altered in obesity (21, 22). Therefore, incorporation of omega-3 into the adipose tissue and the anti-inflammatory effects of omega-3 fatty acids in adipose tissue may also be altered in obesity.
What’s on the research horizon?
Our current understanding of adipose tissue function in obesity comes primarily from studies in cultured cells and animal models of obesity-linked metabolic disease; this has its benefits in that the mechanisms of how and why something is altered in obesity or in response to changes in dietary fat can be investigated more thoroughly. However, single cell types and/or single fatty acids are often used in these experiments which does not reflect the environment of human adipose tissue which is made up of a variety of lipids and a mix of fat and immune cells. There are many human trials in which dietary restriction and exercise interventions have been used to study the effects of weight loss on adipose tissue function but further investigations in humans are required to provide more comprehensive evidence of the influence of different fats on adipose tissue inflammation.
With the prevalence of obesity posing such a burden on our healthcare system, understanding the events resulting in the development of obesity associated diseases, and investigating preventative treatment/lifestyle modification is of great interest. As such, studies into how obesity and changes in dietary fat affect adipose tissue structure and enlargement, fat metabolism, immune and inflammatory responses, and the expression of genes regulating such processes are on-going.
The term ‘anti-inflammatory’ has become a bit of a buzz word in nutrition resulting in a multitude of ‘anti-inflammatory’ foods and supplements we can consume to ensure our bodies remain the inflammation free temples they can be. However, it’s important we think about inflammation in the correct context. Inflammation is part of our defence system and a correct inflammatory response helps protect us against potentially dangerous infections. As discussed above, this type of inflammation is short lived (acute), is resolved by our body and is part of our normal immune function. However, these inflammatory processes become dysregulated in obesity, and other disease states, and an environment of low-grade, constant (chronic) inflammation occurs. It is these conditions that have become the target of anti-inflammatory interventions. Unfortunately there’s no magic, anti-obesity, anti-inflammatory ‘does it all’ food or supplement. Instead I will repeat the age old advice to eat a well-balanced diet that includes healthy fats, particularly omega-3 (from at least one 140 g portion of oily fish per week, see Maeve Hanan’s blog post for plant based alternatives too), move a little bit everyday (150 minutes of moderate or 75 minute of vigorous exercise with strength exercises on 2 days per week (23), stop smoking and avoid high intakes of alcohol, in order to prevent the development of obesity and obesity related diseases
References
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(3) https://www.britishlivertrust.org.uk/about-us/media-centre/facts-about-liver-disease/
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(23) https://www.nhs.uk/live-well/exercise/
