Abstract
Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.
Highlights
Chronic or persistent fatigue is a common, debilitating symptom of several diseases
We propose that this imbalance of energy availability vs. expenditure underlies the experience of fatigue induced by chronic low-grade inflammation
We have here proposed a model of persistent fatigue as a consequence of chronic low-grade inflammation leading to an imbalance in energy availability and expenditure, which can be mediated and maintained by changes in circadian rhythms and sleep
Summary
Chronic or persistent fatigue is a common, debilitating symptom of several diseases. It is one of the most frequently reported symptoms of cancer and cancer treatment (Servaes et al, 2002; Abrahams et al, 2016) and is highly prevalent in several chronic diseases, such as multiple sclerosis, diabetes, and rheumatoid arthritis (Wolfe et al, 1996; Drivsholm et al, 2005; Induruwa et al, 2012; Sanoobar et al, 2015). There is evidence suggesting that low-grade or chronic inflammation (but not acute severe inflammation) can be linked to increases in behavioral-energy expenditure (Vichaya et al, 2014; Lasselin et al, 2017), contributing to the imbalance between energy availability and expenditure and, thereby, leading to fatigue. Several studies in the context of acute, severe inflammation corroborate this hypothesis showing reductions in willingness (motivation) to exert effort, both in rodent models (Larson et al, 2002; Felger et al, 2013; Nunes et al, 2014; Yohn et al, 2016) and in humans (Draper et al, 2017) (Table 1) Results from these and other studies suggest that motivational behavior might be differentially affected in conditions of low-grade inflammation.
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