Inflammation can impair physiological function in almost any organ system and is a factor in a myriad of pathologies (1). Interestingly, weight gain is one of the many complications of chronic inflammation that is still poorly understood by most providers. Hence, it tends to be a much overlooked component in protocols for weight reduction. The importance of understanding the mechanisms behind inflammation and weight gain are crucial to understand if you’re going to unwind the coils that keep many people stuck. 

Now, since this topic is actually more complex than most people think , I decided to dive deeper into the research to try and explain some of the nuances that explain each mechanism of how inflammation induces weight gain and/ or makes it difficult to lose it. So you will find that I’ve included a number of references at the bottom for your viewing pleasure, if you’re into that.

To start it’s important to recap on the mechanism of inflammation and how it develops in the body. Basically, our immune cells or white blood cells as well as other cells of the body have the ability to detect danger. When this occurs they send messages to the rest of the body using chemicals called cytokines. There are a plethora of cytokines that have a multitude of functions that either induce or reduce the activity of other immune cell functions. One in particular is of interest in this conversation known as interleukin-6 or L-6. This particular cytokine is notorious for having a strong impact on both inflammatory reactions and the consequent physiological reactions (1). Thus, for the majority of these topics I will use IL-6 production as the primary inducer of inflammation in the body.

Inflammation Creates Insulin Resistance. 

As inflammation builds due to a chronic trigger such as infections, toxicity, stress, or the like, reactive oxygen species and cytokines build to the point of disrupting cellular communication and energy processing which leads to insulin resistance. As this occurs blood glucose levels rise, and the body produces more insulin. As the cells lose their ability to absorb and utilize energy, sugars get transported to the liver to be synthesized into fatty acids. These fatty acids are then either stored at the liver or directed back into circulation. However, since the cells of the body are not capable of absorbing the fat, the fatty acids are mostly stored outside the cells surrounding the vital organs, thus increasing weight (2). 

Moreover, insulin resistance disrupts mitochondrial function which alters the cells ability to use up energy. As insulin’s actions are blocked on the cells, they struggle to maintain and support the machinery needed to burn up energy. As such, cells that are resistant to insulin have lesser functioning mitochondria and less energy burning capacity, thus an inhibition of fat loss (15). 

So how do you go about determining if you have insulin resistance? 

Determining your body’s level of insulin resistance is pretty simple, and you can screen for this by doing some basic blood work. A few common tests such as fasted glucose and hemoglobin A1C can be indicators of chronically elevated blood sugar but can also come with a number of confounders such as stress, anemia, and genetics. A different and more accurate measure of insulin resistance is fasted insulin which can indicate how much insulin is being produced. Along with fasted glucose, fasted insulin can be utilized to calculate something called the HOMA-IR score. A result less than 1 is optimal, between 2 and 3 is moderately resistant, and above 3 is considered significantly resistant. This measure is touted to have similar accuracy rates to the gold standard methodology of measuring insulin resistance known as the hyperinsulinemic euglycemic clamp (HEC) (13).

Other markers can include the NMR lipoprofile which uses lipid measurements to assess the likelihood of insulin resistance and can be ordered via labcorp. Glycomark is another common assessment similar to the A1C that is touted for more accuracy and can be ordered via Labcorp. 

Inflammation Causes Elevated Cortisol

This is a bit more involved so sit tight. But overall, it makes sense. As it turns out IL-6 has a function in the body that promotes cortisol production (3). Cortisol is a hormone that works to increase the physiological mechanisms necessary to escape danger such as increased blood pressure, blood sugar, and alertness; while decreasing the less necessary physiological processes such as digestion, reproduction, and relaxation. Since cortisol is intended to increase blood sugar and enhance the body’s ability to transport energy to multiple parts of the body, it also induces insulin resistance (4). This allows the blood sugar to travel more readily from the liver to other parts of the body without being absorbed too quickly. However, the issue that occurs during chronic inflammation is that it causes chronic cortisol elevation which induces chronic insulin resistance. As insulin resistance builds, glucose levels will increase, triggering the pancreas to compensate and produce more insulin (5).

The weight gain related effects of cortisol are actually less understood than you might think, and happen to be rather controversial. In animal studies and in vitro studies surrounding the biochemistry of cortisol seem to infer that it induces fat loss and actually has anti-insulinemic effects. Yet, it is well established that elevated cortisol correlations with obesity and abdominal adiposity, as seen in Cushings disease. So why is this?

The interesting truth is that cortisol does induce insulin resistance in muscle but may have insulin sensitizing effects in adipose tissues. In fact, one study found that cortisol may physiologically react differently in humans than it does in animals, hence the contradicting findings between both types of studies. They found that cortisol may sensitize adipose tissue to insulin while it desensitizes muscle to it (6). Insulin triggers lipogenesis and fat accumulation in adipocytes (78).  Thus, this explains how cortisol might induce weight gain as observed in many population studies on chronic stress (9). 

One other nuance that caught my attention was the contradiction in how the pancreatic Beta cells increases insulin in insulin resistant populations, despite cortisol being anti-insulinemic. In fact one study found that across a widespread population, higher levels of cortisol correlated with lower levels of insulin (10). However, it may be that insulin resistance triggers a reaction in the pancreas that is independent of cortisol production and works mainly via the autonomic nervous system. Essentially, the nervous system detects changes in glucose levels an sends messages to the pancreas to start producing insulin (11). However, there may be other mechanisms involved in how other causes of insulin resistance create this affect. For example, inflammation can induce insulin resistance independent of cortisol production just by way of inducing dyslipidemia (12).

So how do you know if you have high cortisol?

The best way to measure cortisol is with salivary tests taken at multiple points throughout the day. This is critical as cortisol is a diurnal hormone which means it changes dramatically throughout the day. Therefore taking it at random times is not an accurate way to assess. You can also measure it via the blood but the body regulates serum cortisol tightly thus it may be more difficult to detect a variation. One test is the Adrenal Stress Profile by Genova Diagnostics and also the Dutch test by Precision Labs.

Inflammation Causes Oxidative Stress Which Increases Adiposity and Reduces Mitochondrial Dysfunction

Chronic inflammation is a known producer of reactive oxygen species which leads to oxidative stress. The immune system responds to perceived signs of invasion and uses reactive oxygen species to both kill off pathogens and signal the production of inflammatory cytokines (16). However, overtime this can induce cellular damage and create a multitude of metabolic issues including insulin resistance (19).

Importantly, however, the immune system is not the only produce of ROS. Mitochondria are also a primary source of ROS and do so via the oxidation of carbohydrates and fatty acids. Thus, excessive nutritional intake of carbohydrates and little provision of antioxidants can further exacerbate these metabolic consequences of oxidative stress. 

Despite the cause, the primary issue of oxidative stress is the excessive production of ROS and the inability to quench it with antioxidants. Thus, it would make sense that biochemically, the body would inhibit ROS production as much as possible to then reduce metabolic damage. In fact, this is exactly what happens as ROS can have direct impacts on the mitochondria’s ability to process energy and instead directs nutrients to be stored as fat in adipose tissue (17). Further, ROS’s also induce the differentiation of adipose tissue, creating more fat cells, and further enhancing the expansion of fat cells making them larger (18). Thus having excessive ROS can function to inhibit fat loss off but also enhances fat gain. 

So how do you go about determining oxidative stress? 

Oxidative stress is not so easy to measure but can be done through a few available tests. One way is to measure urinary F2-isoprostanes which can indicate the production of lipid peroxides or the amount of fats that are damaged by ROS. You can also measure glutathione demand with urinary pyroglutamate which is a byproduct of glutathione wasting. You can also measure organic acids to determine mitochondrial function and nutritional deficiencies that can be implicated in ROS. To measure all of these I usually gravitate towards the Nutreval by Genova which includes all of these biomarkers, although there a few others on the market. 

Other ways that inflammation can inhibit weight loss: 

In addition to the above mechanisms of inflammation inhibited fat loss, there’s a few other possibilities that can play out. 

  1. Inflammation inhibits thyroid hormone production and sensitivity which may induce fat loss inhibition (21). 
  2. In men it can inhibit testosterone production or cause over aromatization into estrogen which can induce weight gain (20). 
  3. It can also impact leptin sensitivity and create leptin resistance which can induce more appetite and also metabolic changes to fat tissue (23).
  4. Finally it can also reduce growth hormone which seems to have an effect on children, although few studies have been performed on adults (22). 

Notice these mechanisms are all related to hormones, which I will be going deeper into in a future blog! Stay tuned!

If you made it this far, thanks for reading! If you’d like to get a deeper evaluation or more support on personalizing a diet to reduce inflammation, click the link below and we’ll get you going!


























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