Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β 2 ‐adrenoceptor mechanisms

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‐ 14 C]‐glucose, [1‐ 14 C]‐palmitate or [2‐ 14 C]‐pyruvate, and BRL37344, β 2 ‐adrenoceptor agonists and selective β‐adrenoceptor antagonists. Formation of 2‐deoxy[1‐ 14 C]‐glucose‐6‐phosphate or 14 CO 2 was measured. 2‐Deoxy[1‐ 14 C]‐glucose uptake and β‐adrenoceptor mRNA were measured in C2C12 cells. Key results: 10 p M BRL37344, 10 p M clenbuterol and 100 p M salbutamol stimulated 2‐deoxyglucose uptake in soleus muscle by 33–54%. The effect of BRL37344 was prevented by 1 μ M atenolol but not by 300 n M CGP20712A or IC3118551, or 1 μ M SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 n M BRL37344 st4mulated 2‐deoxyglucose uptake, whereas 100 n M 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 n M BRL37344 and 10 p M 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 p M 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 n M clenbuterol inhibited 2‐deoxyglucose uptake. British Journal of Pharmacology (2008) 155 , 395–406; doi: fn1 ; published online 16 June 2008