The role of FGF21 in the metabolic adjustments required for exercise capacity

Fatigue is one of the most common and persistent symptoms experienced by patients with various medical conditions. It is characterized by its enduring nature, lack of improvement after a good night's sleep, and interference with daily functioning. The mechanisms behind fatigue remain controversial. In cancer patients, inflammation and mitochondrial dysfunction appear to be the predominant contributors. Mitochondrial dysfunction results from oxidative stress and inflammation. This condition leads to the production and release of soluble mediators known as mitokines, which act in an autocrine, paracrine, and endocrine manner to help the body adapt to the changes in energy metabolism caused by mitochondrial dysfunction. The main mitokines include growth differentiation factor (GDF) 15 and fibroblast growth factor (FGF) 21. We have already gathered evidence highlighting the pivotal role of GDF15 in the behavioral fatigue that arises in response to chemotherapy. In this perspective article, we explore whether the existing knowledge about the role of FGF21 in metabolic adaptations during cellular stress positions this mitokine as a potential candidate for cancer-related fatigue. To do this, we summarize how FGF21 is produced at the level of each organ involved in energy metabolism and how its local and distant effects may influence the capacity to engage in energy-intensive activities such as physical exercise.