How chronic inflammation promotes obesity.

 by Liesa Huppertz
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chronic inflammation, inflammation, inflammation and obesity

Weight gain and obesity is a common problem in western societies. According to the World Health Organisation (WHO) more than 1.9 billion adults were overweight, with 650 million of these being obese. That’s a huge number especially considering the fact that weight gain and obesity are major risk factors for diseases such as type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease or atherosclerosis.

Weight gain and obesity result from a poor diet that contains too many fats and simple carbohydrates, high alcohol consumption and a lack of physical exercise and it can be defined as “too much body fat, characterised by an increase in adipose tissue that is out of proportion with the deposits of protein or carbohydrates” [1].

Chronic inflammation has received more and more attention by the scientific community and rightly so. It’s at the core of so many (deadly) diseases. However, when it comes to obesity and inflammation, it seems like many people are still unfamiliar with this topic. Maybe that’s because we still don’t know all the mechanisms behind this connection and maybe never will.

There are several theories as to how inflammation and obesity are connected. Whichever theory is correct, and I guess they all are to some extent and some may even go hand in hand, they make clear that there is a connection. And this connection is exactly what we want to explore in this article.

How does obesity cause inflammation?

Generally, inflammation is considered to be a good thing as it protects the body. With obesity however, it is accompanied by chronic low-grade inflammation which differs from acute, good inflammation. In chronic, low-grade inflammation there are no typical signs of inflammation but the typical inflammation mediators and signalling pathways that generates disorders are still the same.

So why is obesity the cause for this type of inflammation? There are several theories about that.

1) Obese adipose tissue has always been thought to just be there but not really doing anything. This thought has changed. It is now believed that adipose tissue is indeed a novel endocrine organ that is composed of a variety of cells. These include adipocytes, leukocytes, macrophages, endothelial cells, and fibroblasts (2). All these cells as well as the metabolic tissue play a role in both the hormonal and inflammatory pathways [3].

Especially macrophages, a type of white blood cells, have been found to play a major role in the inflammatory process as they can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production.

Studies on mice showed that obese tissue contained increased levels of the cytokine TNF-Alpha compared to lean tissue [4]. However, it doesn’t seem to be just TNF-Alpha but other inflammatory cytokines, including interleukin (IL)-6, IL-1Beta, CCL2, CRP, monocyte chemoattractant protein-1 (MCP-1) and more [5, 6]. Interestingly, the highest inflammatory scores seem to come from individuals with high levels of visceral adipose tissue, and that is for any given body mass index (BMI).

(2) Besides exhibiting a pro-inflammatory cytokine profile, obese adipose tissue also release high levels of resistin and leptin (pro-inflammatory) which promote insulin insensitivity and lead to a reduction in adiponectin (anti-inflammatory). Leptin is a hormone responsible for the regulation of hunger and satiation. Excess leptin then makes CD4 T cells to produce interferon gamma, a signaling molecule which causes adipocytes to produce major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. It seems that that the inflammatory response is initiated through the dialogue between adipocytes, fat cells, and T cells (7). It seems like MHCII is the real culprit in this scenario as studies on overfed mice show that the ones lacking MHCII experienced less inflammation.

(3) Another theory of how obesity may lead to inflammation is one that looks at the fat cells themselves with regards to stress. As fat mass expands, it becomes suffocated by its own expansion. Due to the increase in the fat cells’ size, they struggle for oxygen supply which puts them in a state of immense distress. This triggers inflammation in the fat tissue which then spills over from fat tissue into the bloodstream (8). Through various blood tests you are then able to measure it with the help of certain inflammatory markers.

(4) Another mechanism may be oxidative stress. Overeating and too much fatty acid cause oxidative stress in the cells. Over time, stress on the mitochondria may cause a low-grade chronic inflammation, often referred to as metaflammation. Through a defense mechanism called autophagy, the body should be able to eliminate damaged mitochondria. However, this mechanism is impaired when through overeating free fatty acids accumulate in the cells, putting huge stress on the mitochondria, our “power plant”. With time, these damaged mitochondria accumulate, which activates the immune response. Inflammation is then caused through exactly this immune response.

How does inflammation cause obesity?

Now that we have established how obesity causes inflammation, you probably also want to know how inflammation causes obesity, am I right?

Here again we have several theories.

(1) We have already talked about how adipose tissue releases excess leptin in the body, remember? And you also still remember what leptin is, right? It’s the hormone that regulates your hunger and satiation. It signals to the hypothalamus in our brain. Leptin does not have so much of an effect on our daily food intake but rather alters our food intake and controls energy expenditure over long time. It has a profound effect when we lose weight and levels of leptin fall which stimulates appetite and increases food intake.

The amount of leptin released into the body correlates directly with the amount of fat cells in your body. So the more fat cells you have, the more leptin is being released into your blood.

Obese people usually have very high levels of leptin due to their brain not responding to leptin the way it should. They just keep eating despite being already full. This concept is called leptin resistance and it may be due to the inflammation of the brain or more specifically, the hypothalamus. When the hypothalamus becomes resistant to leptin, glucose and fat metabolism don’t work well which causes weight gain and insulin resistance. This could also be seen in mice that became obese after being fed a high-fat diet. Their leptin concentrations increased. This increase was accompanied by an increased expression of SOCS-3 (surpressor-of-cytokine-signaling), a potent inhibitor of leptin-signaling [9].

(2) Another theory is connected to insulin resistance which you know may be a result of inflammation, inflammation of your fat tissue to be exact. A specific cytokine, TNF-α, has been shown to cause insulin resistance and also several other proteins like the MCP-1 and CRP are at the root of insulin resistance.

Insulin is a hormone produced in the pancreas. It allows your body’s cells to use glucose, or sugar, from your carbohydrate intake from food for energy or to store it for future use.

When you eat a meal that contains carbs, your blood sugar level rises which signals cells in your pancreas to release insulin into your bloodstream. The amount of insulin released depends on the level of glucose. The higher the level in your blood, the more insulin will be released.

The secreted insulin tells your cells to pick up the sugar from your blood to reduce blood sugar in order to keep them at a good level.

However, sometimes the cells in the body stop responding correctly to insulin, a concept that is called insulin resistance. Even more insulin is being produced to lower blood sugar levels which then leads to high insulin levels in your blood. Over time, cells won’t respond to insulin at all and become increasingly resistant which again results in a rise in both insulin and blood sugar levels. That makes it so much easier for you to store fat as insulin promotes fat storage. Over time, this then can lead to obesity, and eventually heart diseases and diabetes. Insulin resistance on the other hand again causes an increase in pro-inflammatory cytokines that further chronic, low-grade inflammation. Do you see the cycle?

So the question here and in general though is: What came first, the inflammation or the obesity?

Inflammation and obesity - a vicious cycle.

In this article we have seen that inflammation is both the cause and the result of obesity. Once obesity is established, it can further stimulate the production of pro-inflammatory cytokines. This forms a vicious cycle between inflammation and obesity. In other words: fat makes you fat and inflamed and losing weight will help you fight inflammation which again helps to lose more weight. This however, also means that in order to treat obesity, you have to reduce inflammation in your body. The one phenomenon that could be the root cause for so many other diseases.

References:

[1] A.M. Castro∗, L.E. Macedo-de la Concha, C.A. Pantoja-Meléndez. Low-grade inflammation and its relation to obesity and chronic degenerative diseases. Rev Med Hosp Gen Méx. 2017;80(2):101-105

[3] Wozniak SE et al. Adipose tissue: The new endocrine organ? A review article. Digestive Diseases and Sciences. 2009;54(9):1847-1856

[4] Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. 1995. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Investig. 95:2409–15

[5] Andrew S Greenberg and Martin S Obin. Obesity and the role of adipose tissue in inflammation and metabolism1– 4. Am J Clin Nutr 2006;83(suppl):461S–5S (2006).

[6]ShoelsonS,LeeJ,GoldfineA.2006.Inflammationandinsulinresistance.J.Clin.Investig.116:1793–801 Berg AH, Scherer PE. 2005. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 96:939–49

[9] Andrew S Greenberg and Martin S Obin. Obesity and the role of adipose tissue in inflammation and metabolism1– 4. Am J Clin Nutr 2006;83(suppl):461S–5S (2006).

And more:

Margaret F. Gregor and Gökhan S. Hotamisligil. Inflammatory Mechanisms in Obesity. Annu. Rev. Immunol. 2011. 29:415-45. Anders H. Berg, Philipp E. Scherer. Adipose Tissue, Inflammation, and Caridovascular Disease.

Anders H. Berg, Philipp E. Scherer. Adipose Tissue, Inflammation, and Caridovascular Disease.


Disclaimer: Please be aware that I am not a doctor or a medically trained person. What you're reading here is information that I researched and summarized to the best of my knowledge and processed it for your digest. Information stated on iamliesa is for educational purposes only, this information is not to replace advice from your health care practitioner. If you have any concerns about your health, always consult your general practitioner.

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