Ghrelin alleviates depression-like behaviour in rats subjected to high-fat diet and diurnal rhythm disturbance

Abstract

Objectives: In the era of globalization, a sedentary lifestyle is highly linked with obesity and neurobehavioral complications such as depression. While depression is associated with dopamine dysfunction in the ventral tegmental area (VTA), ghrelin enhances the dopaminergic activity in the VTA. Therefore, the present study aimed to assess the effect of ghrelin on depression-like behaviour in rats subjected to a high-fat diet (HFD) and disturbed diurnal rhythm (DDR) for 45 days.

Methods: The neurobehavioral deficits resulting from HFD and DDR in rats, and the behaviour modulation by intra-VTA administration of ghrelin, alone or in combination with ghrelin receptor antagonist were confirmed by evaluation of behavioural parameters in the elevated plus-maze, forced swim test, open field test, and rotarod assessment. Further, the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6, oxidative stress marker malondialdehyde (MDA), and antioxidants enzymes like superoxide dismutase (SOD), reduced glutathione (GSH), and catalase (CAT) were measured.

Results: The levels of TNF-α, IL-1β, IL-6, and MDA were increased in the brain of HFD and DDR exposed rats, while that of SOD, GSH, and CAT were reduced. Intra-VTA ghrelin administration from day 41-45 to the HFD and DDR exposed rats improved cognitive behaviour and physical activity confirming the antidepressant effect. Moreover, ghrelin restored the levels of SOD, GSH and CAT efficiently, and reduced that of MDA, TNF-α, IL-1β and IL-6, which signifies its protective effect.

Conclusion: Overall, this study confirmed the ameliorative effect of ghrelin in HFD- and DDR-induced depression-like behaviour.

Keywords: High-fat diet; cytokines; depression; diurnal rhythm disturbance; ghrelin.

Figure 1

Effect of ghrelin on changes in body weight of rats subjected to HFD and DDR. The data were expressed as mean ± SEM, and analyzed by one-way ANOVA followed by Bonferroni’s post hoc test. #P<0.001 vs. ND+NR; *P<0.001 vs. HFD+DDR. ANOVA, analysis of variance; ANTA, ghrelin antagonist; DDR, disturb diurnal rhythm; GHR, ghrelin; HFD, high-fat diet; ND, normal diet; NR, normal rhythm; SEM, standard error of the mean.

Figure 2

Effect of ghrelin on brain weight of rats subjected to HFD and DDR. The data were expressed as mean ± SEM and analyzed by one-way ANOVA followed by Bonferroni’s post hoc test. #P<0.001 vs. ND+NR; *P<0.001 vs. HFD+DDR. ANOVA, analysis of variance; ANTA, ghrelin antagonist; DDR, disturb diurnal rhythm; GHR, ghrelin; HFD, high-fat diet; ND, normal diet; NR, normal rhythm; SEM, standard error of the mean.

Figure 3

Effect of ghrelin on changes in behavioral parameters (A: % immobility in FST, B: % immobility in OFT, C: % closed arm time in EPM test, D: latency to fall in rotarod test) in HFD and DDR induced depression in rats. The data were expressed as mean ± SEM and analyzed by one-way ANOVA followed by Bonferroni’s post hoc test. #P<0.001 vs. ND+NR; *P<0.001 vs. HFD+DDR. ANOVA, analysis of variance; ANTA, ghrelin antagonist; DDR, disturb diurnal rhythm; GHR, ghrelin; HFD, high-fat diet; ND, normal diet; NR, normal rhythm; SEM, standard error of the mean.

Figure 4

Effect of ghrelin treatment on histopathology of brain of rats subjected to HFD and DDR. A. ND+NR; B. SHAM+DDR; C. ND+DDR; D. HFD+NR; E. HFD+DDR; F. HFD+DDR+GHR; G. HFD+DDR+GHR+ANTA. ANTA, ghrelin antagonist; DDR, disturb diurnal rhythm; GHR, ghrelin; HFD, high-fat diet; ND, normal diet; NR, normal rhythm. Scale bar =100 μ.