METABOLIC AND PHARMACOLOGICAL MODULATION OF OBESTATIN’S EFFECTS IN THE FST

Aims: Obestatin is a 23-amino-acid peptide hormone derived from the same preproghrelin gene as ghrelin. Initially identified as an antagonist to ghrelin's appetite-stimulating effects (Zhang et al., 2005), obestatin is now recognised as a multifunctional hormone that enhances glucose uptake, insulin secretion, adipose tissue differentiation, and improves lipid profiles. While ghrelin has been extensively studied for its roles in energy homeostasis, addiction, and mood regulation, the behavioural profile of obestatin remains poorly understood. Building on our group’s previous evidence of obestatin’s anxiety-inducing properties, this study investigated its impact on depression-like behaviour using the Forced Swimming Test (FST) in male C57BL/6 mice.
Methods: The animals (fed ad libitum and after 12 hours of food restriction) were treated with single doses of intracerebroventricular injection of obestatin (0.5–1.0 -1.5 μg/2 μl aCSF). To explore the underlying mechanisms, to other animal groups we co-administered obestatin and ketamine (2.5 mg intraperitoneally), a general anaesthetic increasingly recognised as a rapid-acting antidepressant.
Results: Our findings have demonstrated that obestatin increased the immobility time in ad libitum-fed mice in the FST, indicating a depressive-like effect. Ketamine decreased the immobility time, blunting the effect of obestatin. Similarly, 12 hours of fasting also reduced the immobility time. The latter results are in line with the ghrelin-related findings in the FST, since ghrelin also has anti-depressive-like effects during fasting.
Conclusions: These data suggest that obestatin acts as a metabolic signal that can drive depressive-like states, offering a potential novel target for future investigations and therapeutic interventions.