β1-adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor knockout mice via nonshivering thermogenesis

Charlotte L. Mattsson, Robert I Csikasz, Ekaterina Chernogubova, Daniel L. Yamamoto, Helena T. Hogberg, Ez-Zoubir Amri, Dana S. Hutchinson, Tore Bengtsson

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39 Citations (Scopus)

Abstract

With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β3-adrenergic receptors. However, vast majorities of β3-adrenergic agonists have so far not been able to stimulate human β3-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β1-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β3- adrenergic receptors. Wild-type and β3-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β3-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β1-adrenergic receptors. Thus, in the absence of β3-adrenergic receptors, β1- adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adiposederived stem cells differentiated into functional brown adipocytes, activation of either β1-adrenergic receptors or β3-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β1-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.

Original languageEnglish
Number of pages11
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume301
Issue number6
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Brown adipose tissue
  • Human multipotent adipose-derived stem cells
  • Obesity
  • Type 2 diabetes
  • Uncoupling protein 1

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