TY - JOUR
T1 - Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β 2-adrenoceptor mechanisms
AU - Ngala, R. A.
AU - O'Dowd, J.
AU - Wang, S. J.
AU - Agarwal, A.
AU - Stocker, C.
AU - Cawthorne, M. A.
AU - Arch, J. R.S.
PY - 2008/10
Y1 - 2008/10
N2 - Background and purpose: Picomolar concentrations of the β 3-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β 2-adrenoceptors. Effects of BRL37344 and β 2-adrenoceptor agonists are compared. Experimental approach: Mouse soleus muscles were incubated with 2-deoxy[1- 14C]-glucose, [1- 14C]-palmitate or [2- 14C]-pyruvate, and BRL37344, β 2-adrenoceptor agonists and selective β-adrenoceptor antagonists. Formation of 2-deoxy[1- 14C]-glucose-6-phosphate or 14CO 2 was measured. 2-Deoxy[1- 14C]-glucose uptake and β-adrenoceptor mRNA were measured in C2C12 cells. Key results: 10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33-54%. The effect of BRL37344 was prevented by 1 μM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 μM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 st4mulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only β 2- adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant. Conclusions and implications: Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via β 2-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake.
AB - Background and purpose: Picomolar concentrations of the β 3-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β 2-adrenoceptors. Effects of BRL37344 and β 2-adrenoceptor agonists are compared. Experimental approach: Mouse soleus muscles were incubated with 2-deoxy[1- 14C]-glucose, [1- 14C]-palmitate or [2- 14C]-pyruvate, and BRL37344, β 2-adrenoceptor agonists and selective β-adrenoceptor antagonists. Formation of 2-deoxy[1- 14C]-glucose-6-phosphate or 14CO 2 was measured. 2-Deoxy[1- 14C]-glucose uptake and β-adrenoceptor mRNA were measured in C2C12 cells. Key results: 10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33-54%. The effect of BRL37344 was prevented by 1 μM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 μM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 st4mulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only β 2- adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant. Conclusions and implications: Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via β 2-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake.
KW - β-adrenoceptor
KW - Atypical β-adrenoceptor
KW - BRL37344
KW - C2C12 cells
KW - Clenbuterol
KW - Fatty acid oxidation
KW - Glucose uptake
KW - Ligand-directed signalling
KW - Salbutamol
KW - Soleus muscle
UR - http://www.scopus.com/inward/record.url?scp=52949115284&partnerID=8YFLogxK
UR - https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/bjp.2008.244
U2 - 10.1038/bjp.2008.244
DO - 10.1038/bjp.2008.244
M3 - Article
C2 - 18552870
AN - SCOPUS:52949115284
SN - 0007-1188
VL - 155
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 3
ER -