Metabolic Signals And Innate Immune Activation In Obesity

February 6, 2020

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 is an evolutionarily conserved system that senses and defends against infection and irritation. Innate immune signaling is a complex cascade that quickly recognizes infectious threats through multiple germline-encoded cell surface or cytoplasmic receptors and transmits signals for the deployment of proper countermeasures through adaptors, kinases, and transcription factors, resulting in the production of cytokines.

As the first response of the innate immune system to pathogenic signals, inflammatory responses must be rapid and specific to establish a physical barrier against the spread of infection and must subsequently be terminated once the pathogens have been cleared. Long-lasting and low-grade chronic inflammation is a distinguishing feature of type 2 diabetes and cardiovascular diseases, which are currently major public health problems.

  1. How does the innate immune system work?

The ability of organisms to mount a response to infectious challenge without prior exposure is regulated by the coordinated interaction of components of the innate immune system. This preformed system is important to respond to exogenous stimuli such as bacterial, viral, and fungal infections. Beyond the initial response to a stressor, the innate immune system coordinates the resolution of inflammation, tissue repair, and the activation of the adaptive immune system to provide memory for future challenges.

While much of our understanding of innate immunity comes from models of infection, it is also clear that immune responses can be triggered by endogenous stimuli. Such mechanisms play a wide role in health and disease from the response to tissue injury, the direction of tissue remodeling, and the response to tumors.

  1. The Innate Immune Response to Obesity

The increased prevalence of obesity and overweight in adults continues to rise and contributes to morbidity and mortality 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). Relevant to this review, increases in inflammatory biomarkers such as C-reactive Protein (CRP) and neutrophilia are seen in obese children as young as 3 years of age (Skinner et al., 2010). 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.

The long term duration of obesity-induced inflammation makes it challenging to describe this unique type of inflammatory activation based on classical models of innate immunity. Applying such models may be inaccurate and insufficient to encompass the events that are triggered by obesity in metabolic tissues such as fat. Furthermore, it is clear that the inflammation generated by obesity is not as high in amplitude as those seen in acute infectious settings (Hotamisligil, 2006). These unique challenges have led to the coining of the term “metal inflammation” 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.

  1. Inflammation as a link between obesity and disease

The interest in obesity-induced inflammation relates to the understanding that inflammatory mechanisms are central to the pathogenesis of diseases such as heart disease that is modified by obesity.

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-related diseases with fundamental alterations in nutrient control derived from pro-inflammatory inputs. 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 a number of physiologic changes in hepatocyte glucose production as well as lipid oxidation and storage. Unusual hepatic lipid accumulation is connected to many obesity-associated illnesses that include non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome. The metabolic changes that occur with hepatic lipid accumulation include hepatic insulin resistance which is related to inflammatory cytokine signals.

4.2 Type 2 Diabetes (T2D)

The regulation of glucose metabolism is securely coordinated between nutrient inputs regulated by the liver and gut, nutrient utilization and storage in muscle and fat, insulin secretion by the pancreas, and central signals from the hypothalamus that coordinate these responses. 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 generation of systemic insulin resistance and hyperglycemia.

  1. 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 comorbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system.

Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling.

Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing 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 comorbidities.

References:

  1. Journal of Biological Chemistry (2013): How Metabolism Generates Signals during Innate Immunity and Inflammation. Retrieved from http://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 from https://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

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