Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase.
Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor gamma agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.
Kola
Blerina
B
Department of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, London EC1M 6BQ, United Kingdom.
Hubina
Erika
E
Tucci
Sonia A
SA
Kirkham
Tim C
TC
Garcia
Edwin A
EA
Mitchell
Sharon E
SE
Williams
Lynda M
LM
Hawley
Simon A
SA
Hardie
D Grahame
DG
Grossman
Ashley B
AB
Korbonits
Márta
M
D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology*; D019281:Dimerization; D013759:Dronabinol / Q000494:pharmacology; D054439:Ghrelin; D006321:Heart / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008099:Liver / Q000201:enzymology; D008297:Male; D008687:Metformin / Q000737:chemistry; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D017202:Myocardial Ischemia; D047495:PPAR gamma / Q000819:agonists; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011619:Psychotropic Drugs / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D002186:Cannabinoids; D054439:Ghrelin; D009097:Multienzyme Complexes; D047495:PPAR gamma; D036361:Peptide Hormones; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D013759:Dronabinol; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases