title: The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.
abstract: The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
authors.affiliation: Clinical Neuroendocrinology Group, Max-Planck-Institute of Psychiatry, Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschöp
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Grübler
authors.forename: Cornelia
authors.initials: C
authors.lastname: Flachskamm
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schubert
authors.forename: Dorothee
authors.initials: D
authors.lastname: Auer
authors.forename: Alexander
authors.initials: A
authors.lastname: Yassouridis
authors.forename: Christa
authors.initials: C
authors.lastname: Thöne-Reineke
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ortmann
authors.forename: Federica
authors.initials: F
authors.lastname: Tomassoni
authors.forename: Cristina
authors.initials: C
authors.lastname: Cervino
authors.forename: Enzo
authors.initials: E
authors.lastname: Nisoli
authors.forename: Astrid C E
authors.initials: AC
authors.lastname: Linthorst
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001066:Appetite / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism; D005231:Fatty Acids, Unsaturated / Q000502:physiology*; D015870:Gene Expression; D007031:Hypothalamus / Q000503:physiopathology; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology; D009765:Obesity / Q000503:physiopathology / Q000628:therapy; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013851:Thinness / Q000503:physiopathology
chemical_list: D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D005231:Fatty Acids, Unsaturated; D008055:Lipids; D009479:Neuropeptides; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D003346:Corticotropin-Releasing Hormone