Endocrine Abstracts

Introduction: Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by GHS-R. 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 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 if 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 μg/kg per bw or CB-1 agonist HU210 20 ng/g per bw and hypothalamic, hepatic and adipose AMPK activity was studied using immunoprecipitation kinase assay.

Results: Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (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% of control, P<0.01) and visceral fat (mesenteric fat (MF): 54.6±16 and 52.0±9.3% of control, P<0.05; epididymal fat (EF): 47.9±12.1 and 45.6±1.7% of control, P<0.05). HU210 significantly inhibited subcutaneous AMPK activity (41.9±7.7% of control, P<0.05) but ghrelin did not have a significant effect. 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% of control, liver: 100.5±11.6 and 116.7±5.4% of control, MF: 132.1±29.9 and 107.1±32.7% of control, EF: 89.8±7.3 and 91.7±18.3% of control, P>0.05). The effects of HU210 on subcutaneous AMPK activity were lost as well (127.0±16.1% of control, P>0.05).

Conclusion: 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.