TY - JOUR
T1 - β1-adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor knockout mice via nonshivering thermogenesis
AU - Mattsson, Charlotte L.
AU - Csikasz, Robert I.
AU - Chernogubova, Ekaterina
AU - Yamamoto, Daniel L.
AU - Hogberg, Helena T.
AU - Amri, Ez Zoubir
AU - Hutchinson, Dana S.
AU - Bengtsson, Tore
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Brown adipose tissue
KW - Human multipotent adipose-derived stem cells
KW - Obesity
KW - Type 2 diabetes
KW - Uncoupling protein 1
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U2 - 10.1152/ajpendo.00085.2011
DO - 10.1152/ajpendo.00085.2011
M3 - Article
C2 - 21878665
AN - SCOPUS:82355183970
VL - 301
SP - E1108-E1118
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0193-1849
IS - 6
ER -