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The Role of Uncoupling Protein 1 in the Metabolism and Adiposity of RIIß-Protein Kinase A-Deficient Mice

Department of Pharmacology, University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: G. Stanley McKnight, Department of Pharmacology, Box 357750, University of Washington, Seattle, Washington 98195-7750. E-mail: mcknight{at}u.washington.edu.

Mice lacking the RIIß regulatory subunit of protein kinase A exhibit a 50% reduction in white adipose tissue stores compared with wild-type littermates and are resistant to diet-induced obesity. RIIß^–/– mice also have an increase in resting oxygen consumption along with a 4-fold increase in the brown adipose-specific mitochondrial uncoupling protein 1 (UCP1). In this study, we examined the basis for UCP1 induction and tested the hypothesis that the induced levels of UCP1 in RIIß null mice are essential for the lean phenotype. The induction of UCP1 occurred at the protein but not the mRNA level and correlated with an increase in mitochondria in brown adipose tissue. Mice lacking both RIIß and UCP1 (RIIß^–/–/Ucp1^–/–) were created, and the key parameters of metabolism and body composition were studied. We discovered that RIIß^–/– mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RIIß^–/– mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RIIß null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RIIß mutant mice.

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