FGF21 deficiency aggravates adipose tissue loss in thermoneutrality-associated cancer cachexia

Cancer-associated cachexia (CAC) is a multifactorial, metabolic wasting syndrome that coincides with cancer malignancies of multiple entities. CAC is characterized by progressive loss of muscle mass and adipose tissue and diminishes therapy responsiveness. Here, we show that the expression of FGF21 is induced in livers of tumor-bearing mice with CAC. FGF21 deficiency promotes weight loss, exacerbates adipose tissue wasting and increases systemic inflammation, pointing towards a protective role of FGF21 in CAC. In line, IL6-mediated STAT3 activation induces FGF21 expression in hepatocytes as well as adipocytes. FGF21 promotes anabolic signaling cascades, increases cellular glucose uptake in response to IL6 exposure and counteracts cytokine-mediated glycerol release, thereby opposing adipose tissue loss in CAC. Eventually, we find that FGF21 is increased in cancer patients with clinical CAC. Together, we reveal a protective role for FGF21 in experimental CAC and identify the protein as a potential biomarker in clinical cachexia.