Objectives- Prolonged supplementation with the β₂-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β₂-adrenoceptor (β₂-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to- especially diabetic- humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to  β₁– and β₃-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1 deficient (UCP1^-/-) mice, lacking thermogenic BAT, vs. wild-type (WT) mice.

Methods– Anaesthetized WT and UCP1^-/-  C57Bl/6 mice were injected with saline or clenbuterol and whole-body oxygen consumption was measured. Furthermore, male WT and UCP1^-/-  C57Bl/6 mice were subjected to 17-weeks of chow feeding, high-fat feeding or high-fat feeding with clenbuterol treatment between week 13-17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively.

Results- Clenbuterol increased oxygen consumption ~2-fold in WT mice. This increase was blunted in UCP1^-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, 2-weeks clenbuterol treatment significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1^-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared to HFD controls and normalized to chow-fed control mice independent of body mass and -composition alterations.

Conclusions- Clenbuterol improved whole-body glucose homeostasis independent of UCP1. Given the low human expression of UCP1, β₂-agonist treatment provides a potential novel route for glucose disposal in diabetic humans.