Targeted gene disruption reveals a leptin-independent role for the mouse beta3-adrenoceptor in the regulation of body composition.
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.
Revelli
J P
JP
Département de Biochimie Médicale, Centre Médical Universitaire, CH-1211 Genève 4, Switzerland.
Preitner
F
F
Samec
S
S
Muniesa
P
P
Kuehne
F
F
Boss
O
O
Vassalli
J D
JD
Dulloo
A
A
Seydoux
J
J
Giacobino
J P
JP
Huarte
J
J
Ody
C
C
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
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