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Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A
D E Cummings1, E P Brandon, J V Planas
1Department of Pharmacology, University of Washington School of Medicine, Seattle, 98195-7750, USA.
Abstract:
Cyclic AMP is an important second messenger in the coordinated regulation of cellular metabolism. Its effects are mediated by cAMP-dependent protein kinase (PKA), which is assembled from two regulatory (R) and two catalytic (C) subunits. In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C gene (encoding C alpha and C beta), expressed in tissue-specific patterns. The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we generated RII beta knockout mice. Here we report that mutants appear healthy but have markedly diminished white adipose tissue despite normal food intake. They are protected against developing diet-induced obesity and fatty livers. Mutant brown adipose tissue exhibits a compensatory increase in RI alpha, which almost entirely replaces lost RII beta, generating an isoform switch. The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enzyme. This causes induction of uncoupling protein and elevations of metabolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulating energy balance and adiposity.
Insights
Mice lacking the RII beta subunit of cAMP-dependent protein kinase (PKA) show reduced adipose tissue but are protected against obesity. This highlights RII beta
Area of Science:
- Molecular Biology
- Cellular Metabolism
- Endocrinology
Background:
- Cyclic AMP (cAMP) is a crucial second messenger regulating cellular metabolism.
- cAMP-dependent protein kinase (PKA) mediates cAMP effects, composed of regulatory (R) and catalytic (C) subunits.
- The RII beta isoform of PKA is notably expressed in adipose tissue and brain.
Purpose of the Study:
- To investigate the physiological functions of the RII beta isoform of PKA.
- To elucidate the role of RII beta in energy balance and adiposity regulation.
Main Methods:
- Generation and analysis of RII beta knockout mice.
- Assessment of adipose tissue mass, metabolic rate, and body temperature.
- Characterization of PKA holoenzyme activity and cAMP binding affinity.
Main Results:
- RII beta knockout mice exhibit diminished white adipose tissue but are protected from diet-induced obesity and fatty liver.
- A compensatory increase in RI alpha occurs in brown adipose tissue, replacing RII beta.
- Mutant adipose tissue shows enhanced cAMP binding and PKA activation, leading to increased uncoupling protein, metabolic rate, and body temperature.
Conclusions:
- The RII beta holoenzyme plays a significant role in regulating energy balance and adiposity.
- Isoform switching in PKA subunits can occur in response to genetic alterations.
- Targeting RII beta may offer therapeutic strategies for metabolic disorders.