Effects of irisin on ovariectomy-induced depression, anxiety, and bodyweight growth in female mice

Hormone replacement therapy (HRT) for postmenopausal syndrome (PMS) carries high risks of undesirable side effects. This study explores irisin as a potential alternative to HRT and investigates the underlying mechanisms. Ovariectomized (OVX) female mice was used as an animal model. The experimental mice were divided into sham, OVX, OVX + irisin (1, 3μg/kg), OVX+ estradiol (0.5mg/kg), and OVX + irisin + compound C (AMPK inhibitor) groups. Results showed that OVX induced depression, anxiety, and bodyweight growth in female mice. These OVX-induced abnormalities were reversed by irisin treatment, while AMPK inhibitor abolished irisin's function, indicating that irisin's therapeutic effects on OVX mice were achieved by activating AMPK. Moreover, irisin could increase pAMPK levels and ameliorate the overexpression of NF-κB and its downstream factors including inflammatory factors (IL-1β, IL-6, and TNF-α) and neurotoxic mediators (COX-2 and iNOS) in the hippocampus, frontal cortex, and serum of the OVX mice. However, irisin did not affect hypothalamus pAMPK level or food intake. These findings indicate that irisin's therapeutic effects on depression and anxiety may be linked to its inhibition of inflammatory factors and neurotoxic mediators in the serum and brain, occurring through the AMPK/NF-κB pathway. Additionally, irisin's effect of reducing bodyweight may be associated with an increase in serum pAMPK level, rather than a direct impact on food intake. Further mechanistic exploration revealed that the beneficial effects of irisin, including both the attenuation of bodyweight gain and the improvement of neurological deficits, are attributed to the activation of αVβ5 receptors.