title: Alpha1- and beta1-adrenoceptor signaling fully compensates for beta3-adrenoceptor deficiency in brown adipocyte norepinephrine-stimulated glucose uptake.
abstract: To assess the relative roles and potential contribution of adrenergic receptor subtypes other than the beta3-adrenergic receptor in norepinephrine-mediated glucose uptake in brown adipocytes, we have here analyzed adrenergic activation of glucose uptake in primary cultures of brown adipocytes from wild-type and beta3-adrenergic receptor knockout (KO) mice. In control cells in addition to high levels of beta3-adrenergic receptor mRNA, there were relatively low alpha1A-, alpha1D-, and moderate beta1-adrenergic receptor mRNA levels with no apparent expression of other adrenergic receptors. The levels of alpha1A-, alpha1D-, and beta1-adrenergic receptor mRNA were not changed in the beta3-KO brown adipocytes, indicating that the beta3-adrenergic receptor ablation does not influence adrenergic gene expression in brown adipocytes in culture. As expected, the beta3-adrenergic receptor agonists BRL-37344 and CL-316 243 did not induce 2-deoxy-d-glucose uptake in beta3-KO brown adipocytes. Surprisingly, the endogenous adrenergic neurotransmitter norepinephrine induced the same concentration-dependent 2-deoxy-D-glucose uptake in wild-type and beta3-KO brown adipocytes. This study demonstrates that beta1-adrenergic receptors, and to a smaller degree alpha1-adrenergic receptors, functionally compensate for the lack of beta3-adrenergic receptors in glucose uptake. Beta1-adrenergic receptors activate glucose uptake through a cAMP/protein kinase A/phosphatidylinositol 3-kinase pathway, stimulating conventional and novel protein kinase Cs. The alpha1-adrenergic receptor component (that is not evident in wild-type cells) stimulates glucose uptake through a phosphatidylinositol 3-kinase and protein kinase C pathway in the beta3-KO cells.
authors.affiliation: The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, SE-106 91 Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Chernogubova
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.forename: Tore
authors.initials: T
authors.lastname: Bengtsson
mesh_terms: D017667:Adipocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D003847:Deoxyglucose / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009638:Norepinephrine / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000172:deficiency* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D000071256:Uncoupling Protein 1; D003847:Deoxyglucose; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D005947:Glucose; D009638:Norepinephrine