Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome

Definition:

• Bioaccumulation: refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. (Wipedia)

Background: Several months ago we discussed an article the describes the results of a study that revealed a link between accumulation of chemicals and diabetes. That study also noted the relationship was correlated to a higher incidence of obesity. In addition, we have recently described that Nrf2 plays a homeostatic role in adipocytes it now appears Nrf2 plays a modulatory role in adipogenesis and when the Nrf2 activity is impaired there is a greater risk for obesity. We have also discussed at length that chemicals bioaccumulate in fat tissue where they produce inflammatory mediators and decrease regulatory and anti-inflammatory proteins such as PPAR-gamma (which when overregulated can contribute to obesity) and adiponectin and it is assumed now this is also true because high-fat diets may impair Nrf2 which influences the control of inflammatory responses mediators such as Tnf-a and MCP-1/CCL2/CCR2, may prevent or delay activation of the antioxidant system. Nrf2 also is responsible for gene expression for proteins important for mitochondrial respiration such as NRF1 and PPAR-a. The latter being a regulatory factor that cooperates with PGC-1a during mitochondrial biogenesis. Insulin resistance also impairs mitochondrial function and is quite a common characteristic that leads to diabetes and obesity.

Other important things we have noted recently are:

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  Sickness syndrome includes a number of behavioral symptoms including fatigue, malaise, increased sensitivity to pain, loss of appetite, anxiety, depression and numerous other symptoms. A recent study has demonstrated that the severity of sickness syndrome depends on the presence or absence of IL-10. If it is present the shorter and less severe the symptoms and if it is absent the patient will experience more severe pathology. In addition, we also noted that MCP-1 is activated by Tnf-a and IL-6 in peripheral tissue to caused neurotransmission in the brain that can incite the inflammatory cascade.
• We also noted that Il-10 is regulated by HO-1 which also is regulated by Nrf2. If the Nrf2 pathway is impaired or inhibited in adipocytes, there is greater opportunity for an elevated inflammatory response in those tissues and the body would have a reduced ability to detoxify an "bioaccumulating" agent that it might be exposed to such as pesticides and other environmental contaminants.
• We have also noted the Nrf2 system can be impaired by exposures to metals, aging factors, other genetic factors, hyperglycemia which is now considered a consequence of environmental or endogenous exposures (H2S).
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  The Nrf2 regulates and is regulated by the aryl hydrocarbon that mediates the detoxification of PAHs and HAHS including dioxin and ingredients in agricultural products. The toxicity of dioxin is mediated through the AhR and is abnormal function may have an extremely important role in toxicity of endotoxin which Maes describes as a pathway to the development of CFS.

A new study has revealed more important details about Il-10 that sheds more light on the symptoms associated with sickness behavior and chronic fatigue syndrome. This new study demonstrates that Il-10 is important for maintaining insulin sensitivity by protecting muscles from obesity-associated macrophage infiltration of inflammatory cytokines and diet-induced inflammatory responses. In the study, it was shown these cytokines include Tnf-a, Il-6, and CCR2. These are markers important in findings related to CFS and fibromyalgia and other environmental illnesses and develop (You can read about MCP-1 here) as part of the stress response from toxicant insults. This study indicates not only that IL-10 may be used as therapy for diabetes but one can suggest future therapies may also target environment illnesses that have presentations of fatigue, muscular pain and sensitivity. A past study demonstrated that Il-10 prevented alterations in Il-6 hepatic insulin action, signaling, and also Il-6 and lipid-induced insulin signaling in skeletal muscle and therefore support the findings from the study noted above. (Kim) Both studies provides evidence of an important role of Nrf2 in regulating metabolic homeostasis by regulating HO-1/IL-10 and demonstrates how its impairment or inhibition can lead to environmental illness.