FGF21 mediates the anti-depressant effects of exercise by coordinating the crosstalk between central and peripheral organs

Physical exercise is an effective antidepression treatment; however, its underlying mechanism remain largely unknown. Fibroblast growth factor (FGF) 21, which is a metabolic hormone secreted by the liver, is critically involved in energy metabolism. Here, we showed that FGF21 knock-out significantly diminished treadmill exercise-elicited anti -depression effect in obese mice, while replenishment with recombinant FGF21 effectively restored depressive phenotypes by suppressing neuroinflammation, enhancing adult neurogenesis and synaptic plasticity in the hippocampus. The anti-depressant effect of FGF21 was attributed to its ability to stimulate adiponectin secretion, which functioned as a downstream effector of FGF21 to confer the anti-depressant effect of exercise. Collectively, these data identify FGF21 as an important player in mediating the anti-depressant effects of exercise on hippocampal neurogenesis and inflammation, possibly by coordinating multi-organ crosstalk among liver, adipose tissue and brain, and also raise the possibility that FGF21 and its agonists may represent a promising therapeutic approach for depression.