Beta2-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men

Abstract

Selective β-adrenoceptor agonism effectively increases metabolic rate and fat oxidation in overweight individuals. The potential for weight loss induced by β-agonists may be greater for R-enantiopure formulations.

Beta2‐adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses

“…This observation underpins the efficacy of formoterol in activating beta 2 ‐adrenergic signaling pathways in skeletal muscle, even after inhalation in therapeutic doses. The formoterol‐induced PKA signaling in skeletal muscle likely explains the apparent effects of formoterol on protein turnover and substrate utilization observed in previous studies …”

“…It should also be noted that compared to rac‐ salbutamol, the muscle:plasma partition coefficient ( K m ) for rac‐ formoterol in the present study was greater than that previously reported in a rodent model for oral dosing of salbutamol (14.3 versus 3.8), acknowledging that the route of administration (oral) and sampling (4 hours) were also different. This greater partitioning could be a pharmacokinetic factor for consideration of formoterol as a preferential therapeutic for muscle wasting and obesity or doping misuse compared to the short acting salbutamol.…”

“…It should also be noted that compared to rac-salbutamol, the muscle:plasma partition coefficient (K m ) for rac-formoterol in the present study was greater than that previously reported in a rodent model for oral dosing of salbutamol (14.3 versus 3.8), 29 acknowledging that the route of administration (oral) and sampling (4 hours) were also different. This greater partitioning could be a pharmacokinetic factor for consideration of formoterol as a preferential therapeutic for muscle wasting and obesity 13,17,33 or doping misuse 34 compared to the short acting salbutamol. While animal models have indicated that slow-twitch dominated muscles (eg, soleus) respond differently to beta 2 -agonists than fasttwitch dominated (eg, extensor digitorum longus), 18 it is unknown whether muscle fiber-type specific differences exist in the disposition of beta 2 -agonist enantiomers.…”

“…Given human skeletal muscle predominantly has a mixed fiber-type composition as compared to rodents, we performed an exploratory analysis of the association between muscle fiber-type composition and enantioselective disposition of (R, utilization observed in previous studies. 13,17,33,34 An important consideration of the present study was that muscle concentrations of formoterol enantiomers were determined 1 hour after inhalation of two repetitive doses of rac-formoterol, consistent with time to reach maximum plasma levels (t max ). 20 Given the observation that the pharmacokinetics of individual formoterol enantiomers in plasma differ, 20,31 it is likely that (R,R)-and (S,S)-formoterol concentrations also exhibit a different time-course in muscle.…”

Enantioselective disposition of (R,R)‐formoterol, (S,S)‐formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

“…This is highly relevant for doping control as formoterol is delivered by inhalation for therapeutic use and a threshold for total formoterol (free and glucuronide conjugate) is used . Supratherapeutic dosing of beta2‐agonists via the inhaled route has been shown to elicit performance‐enhancing effects as well as increase fat oxidation …”