title: Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition.
abstract: Targeted disruption of mouse beta3-adrenoceptor was generated by homologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the beta3-adrenoceptor agonist CL 316,243 on the metabolic rate of homozygous null (-/-) mice. In brown adipose tissue, beta3-adrenoceptor disruption induced a 66% decrease (P < 0.005) in beta1-adrenoceptor mRNA level, whereas leptin mRNA remained unchanged. Chronic energy balance studies in chow-fed mice showed that in -/- mice, body fat accumulation was favored (+41%, P < 0.01), with a slight increase in food intake (+6%, NS). These effects were accentuated by high fat feeding: -/- mice showed increased total body fat (+56%, P < 0.025) and food intake (+12%, P < 0.01), and a decrease in the fat-free dry mass (-10%, P < 0.05), which reflects a reduction in body protein content. Circulating leptin levels were not different in -/- and control mice regardless of diet. The significant shift to the right in the positive correlation between circulating leptin and percentage of body fat in high fat-fed -/- mice suggests that the threshold of body fat content inducing leptin secretion is higher in -/- than in control mice. Taken together, these studies demonstrate that beta3-adrenoceptor disruption creates conditions which predispose to the development of obesity.
authors.affiliation: Département de Biochimie Médicale, Centre Médical Universitaire, CH-1211 Genève 4, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Revelli
authors.forename: F
authors.initials: F
authors.lastname: Preitner
authors.forename: S
authors.initials: S
authors.lastname: Samec
authors.forename: P
authors.initials: P
authors.lastname: Muniesa
authors.forename: F
authors.initials: F
authors.lastname: Kuehne
authors.forename: O
authors.initials: O
authors.lastname: Boss
authors.forename: J D
authors.initials: JD
authors.lastname: Vassalli
authors.forename: A
authors.initials: A
authors.lastname: Dulloo
authors.forename: J
authors.initials: J
authors.lastname: Seydoux
authors.forename: J P
authors.initials: JP
authors.lastname: Giacobino
authors.forename: J
authors.initials: J
authors.lastname: Huarte
authors.forename: C
authors.initials: C
authors.lastname: Ody
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D015152:Blotting, Northern; D001823:Body Composition; D001833:Body Temperature Regulation; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D020738:Leptin; D008297:Male; D051379:Mice; D011506:Proteins / Q000032:analysis / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3; D054411:Receptors, Leptin
chemical_list: D004041:Dietary Fats; D020738:Leptin; D011506:Proteins; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D054411:Receptors, Leptin; C515447:leptin receptor, mouse