Prolonged β 2 -adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1 -/- mice

Prolonged supplementation with the β -agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β -adrenoceptor (β -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 β - and β -ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient ( ) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between and . Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in and , respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in 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 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, β -AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans. Improvements in whole body glucose homeostasis of rodents upon prolonged β -adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β -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 mice, indicating that β -AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.