Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage.

FGF21 is a master regulator of homeostasis of local and systemic lipid, glucose and energy metabolism. Since its discovery a decade ago, significant progress has been made in understanding the basic molecular, cellular and physiological mechanisms underlying its metabolic roles, and characterizing its beneficial pharmacological activities and possible pathological roles in obesity, diabetes, dyslipidemia, fatty liver disease and their collateral complications and tissue damage. Under basal or normal conditions, FGF21 appears to play a dispensable role in metabolism. However, in response to a variety of cellular and metabolic stress, FGF21 is significantly upregulated to serve as a potent catabolic factor leading to the clearance of excessive lipids and glucose, and therefore, antagonizes metabolic and energy imbalance in a negative fashion. Furthermore, FGF21 treatment ameliorates tissue damage resulted from the harmful effects of metabolic abnormalities, which often ensue an oxidative, pro-inflammatory, inflammatory and/or immune stress state, the so-called metaflammation. Most notably, studies focusing on the liver, pancreas, cardio-vasculature and kidney have revealed its significant protective effects against the structural and functional damages induced by the obese, diabetic or other abnormal metabolic conditions. In this review, we will summarize the current progress on the roles of FGF21 against metaflammation and metabolic tissue damage.