Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and beta2-adrenoceptor mechanisms

Background and purpose:

Picomolar concentrations of the β₃-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β₂-adrenoceptors. Effects of BRL37344 and β₂-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, β₂-adrenoceptor agonists and selective β-adrenoceptor antagonists. Formation of 2-deoxy[1-¹⁴C]-glucose-6-phosphate or ¹⁴CO₂ 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 β₂-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 β₂-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.