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

Abstract

Exercise is an effec ve an-depressant treatment; however, its underlying mechanism remains largely unknown. Fibroblast growth factor 21 (FGF21) is a metabolic hormone cri cally involved in energy metabolism. Here, we showed that FGF21 knockout significantly diminished exercise-elicited an-depressant effects, while replenishment with recombinant FGF21 effec vely restored the effects of exercise on allevia on of depression by suppressing neuroinflamma on, enhancing adult neurogenesis and synap c plas city in the hippocampus. However, the FGF21 co-receptor β-klotho was not expressed in hippocampal neurons. The an-depressant property of FGF21 was a ributed to its ability to s mulate adipocyte secre on of adiponec n, which func oned as a downstream effector of FGF21 to confer the an-depressant effects. Collec vely, these data iden fy FGF21 as an important player in media ng the an-depressant effects of exercise, possibly by coordina ng mul-organ crosstalk among liver, adipose ssue and brain, and also raise the possibility that FGF21 and its agonists may represent a promising therapeu c approach for depression.