Prolonged β2-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1−/− mice

S.M.M. van Beek, A. Kalinovich, G. Schaart, T. Bengtsson, J. Hoeks*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Prolonged supplementation with the beta(2)-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via beta(2)-adrenoceptor (beta(2)-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 beta(1)- and beta(3)-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, beta(2)-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 beta(2)-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the beta(2)-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 b2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.
Original languageEnglish
Pages (from-to)E619-E628
Number of pages10
JournalAmerican Journal of Physiology : Endocrinology and Metabolism
Volume320
Issue number3
DOIs
Publication statusPublished - 1 Mar 2021

Keywords

  • beta(2)-adrenergic agonist
  • brown adipose tissue
  • skeletal muscle
  • type 2 diabetes mellitus
  • UCP1

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