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

Abstract

Mice lacking the RII beta 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. RII beta(-/-) 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 RII beta 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 RII beta and UCP1 (RII beta(-/-)/Ucp1(-/-)) were created, and the key parameters of metabolism and body composition were studied. We discovered that RII beta(-/-) mice exhibit nocturnal hyperactivity in addition to the increased oxygen consumption at rest. Disruption of UCP1 in RII beta(-/-) mice reduced basal oxygen consumption but did not prevent the nocturnal hyperactivity. The double knockout animals also retained the lean phenotype of the RII beta null mice, demonstrating that induction of UCP1 and increased resting oxygen consumption is not the cause of leanness in the RII beta mutant mice.

Mouse models of altered protein kinase A signaling

“…This study also analyzed Prkar2b K/K ;Ucp1 K/K double KO mice, which retained the lean phenotype. This observation demonstrated that induction of UCP1 and increased resting oxygen consumption are not the cause of leanness in the Prkar2b K/K mice (Nolan et al 2004). In addition to this, experiments using leptin-deficient Lep ob/ob mice showed that the KO of Prkar2b provided substantial rescue of the obese phenotype.…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…βAR-stimulated lipolysis is impaired but the basal rate of lipolysis is increased in the WAT of Riiβ-knockout mice (Planas et al 1999). In BAT, RIIβ deficiency leads to increases in mitochondrial content and thermogenesis (Nolan et al 2004, Newhall et al 2005. However in human, obesity is associated with reduced RIIβ expression and PKA activity in WAT (Mantovani et al 2009).…”

Deficiency of the RIIβ subunit of PKA affects locomotor activity and energy homeostasis in distinct neuronal populations

“…We previously reported that RΙΙβ KO mice had increased resting oxygen consumption (VO 2 /total body weight), which we hypothesized was related to their elevated basal metabolism and lean phenotype (1,6). To further assess the physiological impact of RIIβ deficiency on metabolism, RIIβ lox/lox animals were subjected to metabolic monitoring for two consecutive days with free access to food and water.…”

“…These mice have an extended lifespan and show diminished age-related metabolic dysfunctions such as fatty liver and insulin resistance (3). Compared with their WT littermates, RIIβ KO mice have normal to slightly increased food intake, a twofold increase in nocturnal physical activity, and a basal metabolic rate (VO 2 consumption) that is higher than WT if calculated based on total body weight (4)(5)(6). RIIβ is highly expressed in the mouse CNS, brown adipose tissue (BAT), and WAT with limited expression elsewhere (1,(7)(8)(9).…”

“…These changes in PKA subunit composition may also alter PKA holoenzyme localization to specific signaling complexes because RIIβ has a much higher affinity for anchoring proteins (AKAPs) than RI (10). RIIβ KO mice have elevated uncoupling protein 1 (UCP-1) in BAT and exhibit enhanced thermogenesis (6). In the WAT, an increased basal lipolysis in RIIβ KO mice was observed, and it was suggested that changes in both BAT and WAT could contribute to the lean phenotype (9).…”