Leptin receptor knockout-induced depression-like behaviors and attenuated antidepressant effects of exercise are associated with STAT3/SOCS3 signaling

- LepRb knockout induced depression-like behaviors and attenuated antidepressant effects of swimming exercise.
- STAT3/SOCS3 pathway was associated with depression-like behaviors in LepRb knockout mice.
- LepRb is an exercise-regulated target for depression.

Relatively little has been known about pathophysiological mechanisms contributing to the development of neuropsychiatric symptoms in the context of metabolic syndrome. Impaired leptin signaling activation in db/db mice has been proposed as a potential link between behavioral and metabolic disorders. Our previous studies have shown that exercise has the beneficial effects on a depression-like and insulin-resistant state in mice. The present study aimed to determine whether and how leptin receptor knockout (db/db) induces depression-like behaviors, and to identify the antidepressant effects of swimming exercise in db/db mice. Our results support the validity of db/db mice as an animal model to study depression with metabolic abnormalities, but fail to confirm the improvement of exercise on depression. LepRb knockout-induced depression-like behaviors are associated with STAT3/SOCS3 signaling but independent of IKKβ/NFκB signaling. Our findings suggest the potential importance of LepRb as an exercise-regulated target for depression, also representing a new target underlying treatment-resistant depression.