Major depressive disorder (MDD), a common psychiatric disease co-morbid with obesity and diabetes, has been one of the most important causes of disability worldwide. Physical exercise by far, is the most effective strategy for the prevention and treatment of MDD. Fibroblast growth factor 21 (FGF-21) is critically involved in energy metabolism and a potential therapeutic agent for treating obesity and its related medical complications. Although the brain is known to be a target of FGF-21 actions, its role in neuropsychological disorders remain unclear. Here, we showed that serum FGF-21 increased progressively with physical exercise and peaked at 3 hours after running, which was 1-2 hours later than that of free fatty acids, suggesting that increased free fatty acids might be the natural agonist of PPARα that induces FGF-21 production during exercise. Real-time PCR analysis further demonstrated that exercise-induced elevation of circulating FGF-21 was predominately from the liver. Furthermore, a series of behavior studies, including tail suspension test, forced swimming test and saccharin preference test uniformly showed that exercise training significantly alleviated depressive symptoms in wild type (WT) mice, which were largely diminished in FGF-21 knockout (KO) mice. Likewise, levels of inflammation markers in the hippocampus were significantly decreased, while synaptic plasticity were notably increased in exercised WT, but not in FGF-21 KO mice, suggesting that inhibition of neuroinflammation and neurogenesis might contribute to the antidepressant effects of FGF-21 during exercise.

In conclusion, FGF-21 is a liver-derived exercise responsive factor mediating the anti-depressant effect of exercise in mice.


Y. Liu: None. S. Yau: None. Y. Wang: None. A. Xu: None.

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