Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism

Introduction: Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids. Aims: Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity. Methods: Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500. ng/g bodyweight or CB1 agonist HU210 20. ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay. Results: Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean ± SEM, 122.5 ± 5.2% and 128 ± 11.6% of control, p<0.05) and inhibited it in liver (55.1 ± 4.8% and 62.2 ± 14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6 ± 16% and 52.0 ± 9.3%, p<0.05; epididymal fat (EF): 47.9 ± 12.1% and 45.6 ± 1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9 ± 7.7% and 87.4 ± 13.3%, liver: 100.5 ± 11.6% and 116.7 ± 5.4%, MF: 132.1 ± 29.9% and 107.1 ± 32.7%, EF: 89.8 ± 7.3% and 91.7 ± 18.3%, p>0.05). Conclusions: Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.