&bgr;1 Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice.

Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple &bgr;-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the &bgr;1 isoform in energy homeostasis. First, the 30 min i.v. infusion of norepinephrine (NE) or the &bgr;1 selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the &bgr;1 gene (KO of &bgr;1 adrenergic receptor (&bgr;1KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, &bgr;1KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, &bgr;1KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the &bgr;1 signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis. [ABSTRACT FROM AUTHOR]