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

摘要

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 beta(3)-adrenergic receptors. However, vast majorities of beta(3)-adrenergic agonists have so far not been able to stimulate human beta(3)-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by beta(1)-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking beta(3)-adrenergic receptors. Wild-type and beta(3)-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. beta(3)-knockout mice were able to survive both acute and prolonged cold exposure due to activation of beta(1)-adrenergic receptors. Thus, in the absence of beta(3)-adrenergic receptors, beta(1)-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 adipose-derived stem cells differentiated into functional brown adipocytes, activation of either beta(1)-adrenergic receptors or beta(3)-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, beta(1)-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.