title: Alterations in the hippocampal endocannabinoid system in diet-induced obese mice.
abstract: 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 processes.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Massa
authors.forename: Giacomo
authors.initials: G
authors.lastname: Mancini
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Frauke
authors.initials: F
authors.lastname: Steindel
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Stéphane H R
authors.initials: SH
authors.lastname: Oliet
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D008071:Lipoprotein Lipase / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D004041:Dietary Fats; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase; C078814:anandamide
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