Alterations in the hippocampal endocannabinoid system in diet-induced obese mice.

F. Massa, G. Mancini, H. Schmidt, F. Steindel, K. Mackie, C. Angioni, S. H. R. Oliet, G. Geisslinger, B. Lutz
Journal of Neuroscience. 2010-05-05; 30(18): 6273-6281
DOI: 10.1523/jneurosci.2648-09.2010

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The endocannabinoid (eCB) system plays central roles in the regulation of food
intake and energy expenditure. Its alteration in activity contributes to the
development and maintenance of obesity. Stimulation of the cannabinoid receptor
type 1 (CB(1) receptor) increases feeding, enhances reward aspects of eating, and
promotes lipogenesis, whereas its blockade decreases appetite, sustains weight
loss, increases insulin sensitivity, and alleviates dysregulation of lipid
metabolism. The hypothesis has been put forward that the eCB system is overactive
in obesity. Hippocampal circuits are not directly involved in the neuronal
control of food intake and appetite, but they play important roles in hedonic
aspects of eating. We investigated the possibility whether or not diet-induced
obesity (DIO) alters the functioning of the hippocampal eCB system. We found that
levels of the two eCBs, 2-arachidonoyl glycerol (2-AG) and anandamide, were
increased in the hippocampus from DIO mice, with a concomitant increase of the
2-AG synthesizing enzyme diacylglycerol lipase-alpha and increased CB(1) receptor
immunoreactivity in CA1 and CA3 regions, whereas CB(1) receptor agonist-induced
[(35)S]GTPgammaS binding was unchanged. eCB-mediated synaptic plasticity was
changed in the CA1 region, as depolarization-induced suppression of inhibition
and long-term depression of inhibitory synapses were enhanced. Functionality of
CB(1) receptors in GABAergic neurons was furthermore revealed, as mice
specifically lacking CB(1) receptors on this neuronal population were partly
resistant to DIO. Our results show that DIO-induced changes in the eCB system
affect not only tissues directly involved in the metabolic regulation but also
brain regions mediating hedonic aspects of eating and influencing cognitive


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