Metabolic underpinnings of cancer-related fatigue

Abstract

Cancer-related fatigue (CRF) is one of the most prevalent and detrimental complications of cancer. Emerging evidence suggests that obesity and insulin resistance are associated with CRF occurrence and severity in cancer patients and survivors. In this narrative review, we analyzed recent studies including both preclinical and clinical research on the relationship between obesity and/or insulin resistance and CRF. We also describe potential mechanisms for these relationships, though with the caveat that because the mechanisms underlying CRF are incompletely understood, the mechanisms mediating the association between obesity/insulin resistance and CRF are similarly incompletely delineated. The data suggest that, in addition to their effects to worsen CRF by directly promoting tumor growth and metastasis, obesity and insulin resistance may also contribute to CRF by inducing chronic inflammation, neuroendocrinological disturbance, and metabolic alterations. Furthermore, studies suggest that patients with obesity and insulin resistance experience more cancer-induced pain and are at more risk of emotional and behavioral disruptions correlated with CRF. However, other studies implied a potentially paradoxical impact of obesity and insulin resistance to reduce CRF symptoms. Despite the need for further investigation utilizing interventions to directly elucidate the mechanisms of cancer-related fatigue, current evidence demonstrates a correlation between obesity and/or insulin resistance and CRF, and suggests potential therapeutics for CRF by targeting obesity and/or obesity-related mediators.

Keywords: cancer metabolism; cancer-related fatigue.

Graphical abstract

Figure 1.

Obesity is closely correlated with cancer-related fatigue in human patients. Obesity contributes to CRF in patients with cancer by either promoting tumor growth and metastasis or enhancing CRF development, including inducing chronic inflammation, neuroendocrinological disruptions, and systemic or local metabolic alterations. These factors result in either reduced motivation or impaired muscle contraction. Such physical disturbances are shown in blue circles in the figure. In addition, obesity also indirectly affects CRF via emotional disturbance, for instance depression and anxiety, as shown in pink circles in the figure. Cognitive disruptions, especially nociception shown in the yellow circle, are also found in patients with obesity and affecting CRF. Eventually, obesity worsen insomnia, which correlate with CRF. Food intake is another factor related to CRF, as malnutrition is a major cause of CRF, wherein patients with obesity often comprise altered appetite. These behavioral alterations are shown in green in the figure. Created with BioRender.com. CRF, cancer-related fatigue.

Figure 2.

The direct effects of obesity on cancer-related fatigue in patients with cancer. Obesity directly affects CRF development in patients with cancer. First, obesity induce chronic inflammation, characterized as elevation of proinflammatory cytokines and reduced secretion of anti-inflammatory cytokines from immune cells within adipose tissue after activation of their TLRs. These cytokines induce disruptions in neurological circuits related to motivation and motion within central nervous system, resulting in fatigue feeling in patients with cancer. Also, patients with obesity comprise increased sympathetic activity and reduced parasympathetic activity, as well as disrupted diurnal cortisol rhythm. Such neuroendocrinological disruptions also lead to disturbance in central nervous system and fatigue feelings. Last but not least, systemic metabolism in patients with obesity is altered, which also contribute to the development of CRF. For instance, adipocytes in patients with obesity have higher lactate production, wherein elevated circulating lactate reduces motivation of movement. Metabolic alteration in skeletal muscle, including amino acid metabolism and ATP synthesis, directly affect muscle contraction and hence impair movements. Created with BioRender.com. CRF, cancer-related fatigue; TLR, Toll-like receptor.

Figure 3.

Obesity promotes tumor progression and metastasis. Obesity directly promotes tumor proliferation and metastasis, which is positively correlated with severity of CRF in patients with cancer. In one hand, obesity enhances tumor cell proliferation. Obesity is often comorbid with insulin resistance. PI3K from activated insulin mitogenic signaling pathway activates MAPK signaling pathway, promoting tumor survival, growth, and proliferation. Also, AKT is activated, which inhibits BAD and FOXO and their downstream effector, inhibiting cell apoptosis. In addition, metabolic stress induced by obesity activates mTOR signaling pathways in tumor cell, promoting tumor cell proliferation and metabolism. Furthermore, activated AKT inhibits the activity of JNK signal, which is activated by proinflammatory cytokines and results in cell apoptosis. On the other hand, adipose tissue promotes tumor metastasis. Neutrophils residing in adipose tissue comprise increased ROS production in patients with obesity, which compromises the tight junction in endothelial tissue and favors metastatic tumor cell evasion. Furthermore, adipose tissue promotes tumor cell survival and proliferation by secreting cytokines and hormones that activates JAK/STAT or PI3K/AKT signaling pathway within tumor cells. Also, free fatty acid within adipose tissue recruits immune cells into adipose tissue and secretes proinflammatory cytokines that not only promote tumor proliferation but also activates VEGF/VEGFR signaling pathway and enhances angiogenesis in metastatic tumor. Created with BioRender.com. CRF, cancer-related fatigue; FFAs, free fatty acids; ROS, reactive oxygen species; TLR, Toll-like receptor.