Metabolic response to various beta-adrenoceptor agonists in beta3-adrenoceptor knockout mice: evidence for a new beta-adrenergic receptor in brown adipose tissue.
The beta3-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to beta-adrenoceptor stimulation were compared in adipose tissues of beta3-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. In BAT of wild type mice (-)-norepinephrine maximally stimulated MO2 4.1+/-0.8 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (dobutamine 5.1+/-0.3, terbutaline 5.3+/-0.3 and CL 316,243 4.8+/-0.9 fold, respectively); in BAT of beta3-adrenoceptor knockout mice, the beta1- and beta2-responses were fully conserved. In BAT of wild type mice, the beta1/beta2-antagonist and beta3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7+/-0.4 fold). In beta3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical beta-adrenoceptor, distinct from the beta1-, beta2- and beta3-subtypes and referred to as a putative beta4-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. In isolated white adipocytes of wild type mice, (-)-epinephrine maximally stimulated lipolysis 12.1+/-2.6 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (TO509 12+/-2, procaterol 11+/-3, CL 316,243 11+/-3 fold, respectively) or with CGP 12177 (7.1+/-1.5 fold). In isolated white adipocytes of beta3-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the beta1-, beta2-, beta3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.
Départment de Biochimie Médicale, Centre Médical Universitaire, Geneva, Switzerland.
F
F
Preitner
P
P
Muzzin
J P
JP
Revelli
J
J
Seydoux
J
J
Galitzky
M
M
Berlan
M
M
Lafontan
J P
JP
Giacobino
D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004837:Epinephrine / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D005990:Glycerol; C033394:CGP 12177; D004837:Epinephrine