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Metabolic signals and innate immune activation in obesity

Important Points:

  • Obesity
  • Inflammation
  • Innate immune activation
  • Non-alcoholic fatty liver disease
  • Infection

Metabolic signals and innate immune activation in obesity

The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as Type 2 Diabetes and Atherosclerosis.

 1. The innate immune system

The innate immune system was made to sense and defend against infection and irritation. It sends signals creating a cascade of action from recognizing a threat of infection or irritation to the right cells which respond with the proper countermeasures. As the front line of defense, the innate immune system must be swift in recognizing these threats in order to establish a barrier that will keep the rest of the body healthy and disease free, and then it must provide a way to release that barrier once the threat has dissipated. When it sends many signals to set up barriers and not enough signals to remove the barriers, chronic inflammation is established. Long-lasting and low-grade chronic inflammation can often lead to Type 2 Diabetes and cardiovascular diseases.

2. How does the innate immune system work?

The innate immune system guards against all threats of infection and irritation even ones it hasn’t seen before including bacterial, viral, and fungal infections or a break in the protective barrier of any organ, especially skin, which causes irritation. Its response is swift, within about four hours, and coordinates the following components:

  • T-cells and B-cells bind antibodies to antigens that have invaded the body
  • Phagocytes essentially “eat” infectious organisms to get rid of them
  • Cytokines kick in with the inflammatory response which may include pain, tenderness, redness and warmth due to increased blood flow, or fever

Once the infection or irritation is contained, the innate immune system will work on its resolution including tissue repair and activation of the process by which antibodies are made; these antibodies will prevent an infection by the same organism later. While much of our understanding of this system comes from what we know about our responses to infection, it is thought that immune responses can also be triggered by internal problems such as inflammation.

3. The Innate Immune Response to Obesity

The increased prevalence of obesity and overweight in adults continues to rise and contributes to disease and death that is estimated to cost $147 billion dollars a year in the U.S. (Finkelstein et al., 2009) and up to 0.6% of the gross domestic product of European countries (Muller-Riemenschneider et al., 2008). More ominous is the high rates of childhood obesity which is a strong predictor of adult obesity (Lee et al., 2009). This has also shifted the prevalence of adult diseases such as type 2 diabetes and pre-diabetes into childhood and has generated new treatment and prevention challenges (Lee, 2006Lee et al., 2006). One study (Skinner et al., 2010) showed an increase in inflammatory bio-markers in obese children as young as 3 years of age. This indicates that many of the origins of obesity-induced inflammation may actually be initiated during childhood. Therefore, many people will face a lifetime threat to health from obesity.

Because the innate immune system is supposed to be relatively short acting, the response to obesity-induced inflammation is hard to compare. Applying the same models may be inaccurate and insufficient to fully explain how the body is affected. Furthermore, it is clear that the inflammation generated by obesity does not require as swift and dedicated a response as those seen in acute infectious settings (Hotamisligil, 2006). These unique challenges have led to the coining of the term “metainflammation” to describe the chronic low-grade inflammatory events that occur in obesity and its associated diseases.

A frequently asked question is why would obesity trigger an immune response? For the most part, this question remains unanswered, but one answer to this may lie in the fact that many of the key regulators of metabolism also play critical roles in regulating inflammatory responses.

4. Inflammation as a link between obesity and disease

The interest in obesity-induced inflammation relates to the understanding that inflammatory mechanisms are aid in the development of diseases found more often in those who are obese such as heart disease.

It is impossible to cover the scope of all of these diseases so we will focus our attention on the inflammatory mechanisms of fatty liver disease and Type 2 Diabetes. This will set the stage for future discussion of the innate immune components activated in obesity. I will highlight both clinical and pre-clinical studies in animal models of obesity that have built our understanding of the mechanisms that drive obesity-associated diseases.

4.1 Non-alcoholic Fatty Liver Disease (NAFLD)

The liver plays a critical role in the regulation of glucose and lipids levels in the blood. Obesity generates changes in the function of the body; glucose production and the breakdown (oxidation) and storage of fats specifically in the liver. Unusual fat accumulation in the liver is connected to many obesity-associated illnesses that include non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome. The metabolic changes that occur with this fat accumulation include insulin resistance propagated by the liver which is related to inflammatory cytokine signals.

4.2 Type 2 Diabetes (T2D)

The regulation of glucose metabolism is securely coordinated from the hypothalamus between nutrients regulated by the liver and gut, the use of these nutrients and storage in muscle and fat, and insulin secreted by the pancreas. The dysregulation of almost all of these processes with obesity is now known to be associated with the activation of innate pro-inflammatory pathways. The net result of this is the rise of systemic insulin resistance and hyperglycemia.

5. Why obesity affects the innate immune system

The blend of a sedentary lifestyle and surplus energy intake has led to an increased occurrence of obesity which constitutes a major risk factor for several diseases including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that one main feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation, a result of the innate immune system being activated.

Recent evidence suggests that activation of the innate immune system in the course of obesity starts with an elevation in metabolic signals which sets up a pattern of recognition receptors and leads to stimulation of critical inflammatory signaling cascades which interfere with insulin signaling.

Exercise is one of the main prescribed interventions in obesity management because it helps improve insulin sensitivity and reduce obesity-induced chronic inflammation. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its related diseases.

References:

  1. Journal of Biological Chemistry (2013): How Metabolism Generates Signals during Innate Immunity and Inflammation. Retrieved fromhttp://www.jbc.org/content/288/32/22893.full.html
  2. Physiological reviews (2018): Innate Immune Signaling and Its Role in Metabolic and Cardiovascular Diseases. Retrieved fromhttps://www.physiology.org/doi/abs/10.1152/physrev.00065.2017
  3. NCBI (2012): Innate Immune Activation in Obesity. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888776/
  4. NCBI (2015): Metabolic signals and innate immune activation in obesity and exercise. Retrieved from

https://www.ncbi.nlm.nih.gov/pubmed/25825956