Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β₂‐adrenoceptor mechanisms

Abstract

Background and purpose: Picomolar concentrations of the b 3 -adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via b 2 -adrenoceptors. Effects of BRL37344 and b 2 -adrenoceptor agonists are compared. 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 mM atenolol but not by 300 nM CGP20712A or ICI118551, or 1 mM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 stimulated 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 b 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 b 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.

Adrenergic receptors and metabolism: role in development of cardiovascular disease

“…Short- and long-term stimulation of the β 2 -AR has been associated with the modulation of fatty acid and glucose metabolism (Philipson, 2002). Indeed, acute treatment of myocytes in vitro or skeletal muscle ex vivo with β 2 agonists induces a significant increase in glucose uptake, reaching comparable levels to insulin stimulation (Nevzorova et al, 2002, 2006; Ngala et al, 2008). A putative mechanism for these evidence would involve the activation of PI3K and its downstream signal pathway (Zhu et al, 2001; Jo et al, 2002; Perez-Schindler et al, 2011; Zhang et al, 2011) and in particular the phosphorylation and inactivation of TBC1D4 (also known as Akt substrate of 160 kDa, AS160) by Akt (Sakamoto and Holman, 2008).…”

Adrenergic signaling in heart failure and cardiovascular aging

“…Short- and long-term stimulation of the β 2 AR has been associated with the modulation of fatty acid and glucose metabolism [98]. Indeed, acute treatment with β 2 AR agonists of myocytes or skeletal muscle increases glucose uptake to levels comparable to those seen after insulin stimulation [99]. …”

Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle

“…Ideally, this involves signaling pathways that are not dependent on insulin. Although activation of adrenoceptors in vitro has been shown to stimulate glucose uptake in skeletal muscle (2)(3)(4)(5)(6)(7)(8)(9)(10), the signaling pathways involved and the potential for treating type 2 diabetes have been unclear. In vivo, sympathetic effects on glucose homeostasis are complex, being influenced by glucose outflow from the liver, insulin release from the pancreas, as well as glucose uptake into peripheral tissues such as white fat, brown fat, and muscle.…”

“…Long-term activation of b 2 -adrenoceptors in rats causes skeletal muscle hypertrophy (11), leading to decreased plasma insulin levels, increased insulin sensitivity, and improved glucose tolerance (12,13); in humans, there are beneficial metabolic changes (14,15), although some b-blockers exacerbate diabetes (16). Despite this circumstantial evidence (2)(3)(4)(5)(6)(7)(8)(9)(10), the mechanisms involved in adrenergic facilitation of glucose uptake in peripheral tissues and their potential therapeutic role are poorly understood.…”