Metabolic status regulates the efficacy of ghrelin’s actions in the brain. For example, high fat feeding induces ghrelin resistance in NPY/AgRP neurons whereas negative energy balance accentuates central ghrelin sensitivity. The mechanisms that underpin increased ghrelin sensitivity during negative energy balance remain unknown but may underlie numerous functions of ghrelin in the brain. Blood glucose is a signal of metabolic state, therefore we examined whether acute manipulation of glucose availability affects ghrelin sensitivity.

We pre-treated mice with either ip glucose or ip 2-deoxyglucose (2DG) to induce acute hyperglycemia and glucopenia (reduced cellular glucose availability). 30 minutes later, we injected ghrelin into the ventricular system or the ventral tegmental area (VTA), two key sites regulating ghrelin-induced feeding. Glucose pre-treatment abolished the ghrelin-induced feeding response at both brain sites, whereas pre-treatment with 2DG, enhanced the feeding response to ghrelin injected at either brain site. This effect was additive, showing no signs of synergistic interaction. Fos expression in AgRP neurons was increased by ICV ghrelin but the magnitude of this increase was unaffected by either glucose or 2DG pre-treatment. These results suggest glucose availability modulates ghrelin’s responsiveness through pathways other than traditional signalling in AgRP neurons.

 Considering HFD causes ghrelin resistance, we wondered if treatment of HFD-fed mice with 2DG increased ghrelin sensitivity due to reduced cellular glucose availability. 2DG increased blood glucose levels and induced feeding to a similar degree in both HFD-fed and chow-fed mice. Ghrelin was ineffective at inducing food intake in HFD-fed mice, and pre-treatment with 2DG did alter this, therefore ghrelin resistance is not alleviated by 2DG.

Our results point to divergent short and long-term mechanisms regulating ghrelin responsiveness. Glucose availability predicts ghrelin responsiveness in the short-term, however, loss of ghrelin sensitivity caused by HFD cannot be restored by acute manipulation of glucose availability.