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Review
. 2018 Apr 26:12:78.
doi: 10.3389/fnbeh.2018.00078. eCollection 2018.

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure

Tamara E Lacourt  1 , Elisabeth G Vichaya  1 , Gabriel S Chiu  1 , Robert Dantzer  1 , Cobi J Heijnen  1
Affiliations
Review

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure

Tamara E Lacourt et al. Front Behav Neurosci. .

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.

Keywords: cancer-related fatigue; chronic fatigue syndrome; cytokines; effort; energy balance; metabolism; motivation.

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Figures

Figure 1
Figure 1
Schematic overview of proposed pathways from inflammation to fatigue. Inflammation affects cellular energy availability through its effects on metabolism. Inflammation can at the same time affect energy expenditure, both through increased energy demand by the immune system and through changes in motivation-driven energy expenditure. Both pathways can be partially mediated by altered circadian rhythms and disturbed sleep. The resulting imbalance in energy availability and expenditure underlies the experience of fatigue.
Figure 2
Figure 2
(A) Carbohydrates can be stored as glycogen, which can be rapidly utilized for fast energy production. As storage is limited to a handful of organs, mainly the liver and skeletal muscles, sustained usage of glycogen will deplete stores in a few h. During catabolism, glycogen is first broken down into glucose molecules that enter into glycolysis, yielding pyruvate. The process of glycolysis yields a low amount of ATP and NADH. After the addition of a CoA group, pyruvate (now acetyl-CoA) enters into the TCA cycle to produce NADH and FADH2. (B) In contrast to carbohydrate storage, storage of lipids, in the form of triglycerides, is virtually limitless. Catabolism of lipids is a slow process and is therefore mainly utilized during prolonged energy need (i.e., when carbohydrate storage is expended). The process yields fatty acids and glycerol. The addition of a CoA group to fatty acids generates acyl-CoA, which is carried into the mitochondria via the carrier protein carnitine. Once inside the mitochondria, acyl-CoA is catabolized via β-oxidation to produce NADH and FADH2. Glycerol can enter into the end steps of glycolysis or is reprocessed to form glucose (i.e., gluconeogenesis). (C) Proteins can be broken down in smaller polypeptides or amino acids during ATP production but cannot be stored. As proteins are required for biological functions other than ATP production, they are thought to be used for ATP production only in conditions of extreme demand, such as sickness or chronic inflammation. Proteins used for ATP production do not go through glycolysis, but instead are converted to TCA metabolites or pyruvate. (D) NADH and FADH2 generated by glycolysis, β-oxidation, and the TCA cycle are converted via the electron transport chain (ETC) in the mitochondria. The ETC is a series of 5 protein complexes that work in synchrony to produce ATP. This process, called oxidative phosphorylation, requires oxygen. CoQ10 functions as an electron carrier between the complexes of the electron transport chain. (E) In the absence of oxygen, or when mitochondria are impaired, glycolysis is the dominant energy-producing metabolic pathway. In order for glycolysis to continue, however, NAD+, a secondary substrate along with glucose, must be regenerated from NADH. To do so, pyruvate is converted into lactate, an energy-requiring mechanism that utilizes NADH and thus decreases overall ATP production. ATP, adenosine triphosphate; CoA, coenzyme A; CoQ10, coenzyme Q10; ETC, Electron transport chain; FADH2, flavin adenine dinucleotide; NADH and NAD+, forms of nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.
Figure 3
Figure 3
Schematic overview of changes in metabolism within immune cells during acute (Left) and chronic (Right) inflammation. During acute inflammation, immune cells increase glycolysis while decreasing the TCA cycle for fast generation of ATP. During chronic low-grade inflammation, insulin resistance leads to a decrease in glucose uptake and glycolysis. To compensate, the body increases lipid and protein metabolism for ATP production. ATP, adenosine triphosphate; FADH2, flavin adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; TCA, tricarboxylic acid.
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