Role of the endocannabinoid system in obesity induced by neuropeptide Y overexpression in noradrenergic neurons.
OBJECTIVE
Endocannabinoids and neuropeptide Y (NPY) promote energy storage via central and peripheral mechanisms. In the hypothalamus, the two systems were suggested to interact. To investigate such interplay also in non-hypothalamic tissues, we evaluated endocannabinoid levels in obese OE-NPY(DβH) mice, which overexpress NPY in the noradrenergic neurons in the sympathetic nervous system and the brain.


METHODS
The levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were measured in key regulatory tissues, that is, hypothalamus, pancreas, epididymal white adipose tissue (WAT), liver and soleus muscle, over the development of metabolic dysfunctions in OE-NPY(DβH) mice. The effects of a 5-week treatment with the CB1 receptor inverse agonist AM251 on adiposity and glucose metabolism were studied.


RESULTS
2-AG levels were increased in the hypothalamus and epididymal WAT of pre-obese and obese OE-NPY(DβH) mice. Anandamide levels in adipose tissue and pancreas were increased at 4 months concomitantly with higher fat mass and impaired glucose tolerance. CB1 receptor blockage reduced body weight gain and glucose intolerance in OE-NPY(DβH) to the level of vehicle-treated wild-type mice.


CONCLUSIONS
Altered endocannabinoid tone may underlie some of the metabolic dysfunctions in OE-NPY(DβH) mice, which can be attenuated with CB1 inverse agonism suggesting interactions between endocannabinoids and NPY also in the periphery. CB1 receptors may offer a target for the pharmacological treatment of the metabolic syndrome with altered NPY levels.
1] Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland [2] Drug Research Doctoral Program, University of Turku, Turku, Finland.
L H
LH
Vähätalo
Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
S T
ST
Ruohonen
Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
S
S
Mäkelä
1] Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland [2] Drug Research Doctoral Program, University of Turku, Turku, Finland.
L
L
Ailanen
Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
A-M
AM
Penttinen
Department of Biostatistics, University of Turku, Turku, Finland.
T
T
Stormi
Department of Biostatistics, University of Turku, Turku, Finland.
T
T
Kauko
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy.
F
F
Piscitelli
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy.
C
C
Silvestri
1] Department of Pharmacology, Drug Development and Therapeutics and Turku Center for Disease Modeling, University of Turku, Turku, Finland [2] Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
E
0000000334210367
E
Savontaus
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy.
V
V
Di Marzo