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, versus wild-type (WT) mice. Anesthetized 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-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold 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, low-dose clenbuterol treatment for 2 wk 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 with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β₂-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged β₂-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β₂-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1^-/- mice, indicating that β₂-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.

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