title: Differentially regulated protein kinase A (PKA) activity in adipose tissue and liver is associated with resistance to diet-induced obesity and glucose intolerance in mice that lack PKA regulatory subunit type IIα.
abstract: The cAMP-dependent protein kinase A (PKA) signaling system is widely expressed and has a central role in regulating cellular metabolism in all organ systems affected by obesity. PKA has four regulatory (RIα, RIIα, RIβ, RIIβ) and four catalytic (Cα, Cβ, Cγ, Prkx) subunit isoforms that have tissue-specific expression profiles. In mice, knockout (KO) of RIIβ, the primary PKA regulatory subunit in adipose tissue or knockout of the catalytic subunit Cβ resulted in a lean phenotype that resists diet-induced obesity and associated metabolic complications. Here we report that the disruption of the ubiquitously expressed PKA RIIα subunit in mice (RIIαKO) confers resistance to diet-induced obesity, glucose intolerance, and hepatic steatosis. After 2-week high-fat diet exposure, RIIαKO mice weighed less than wild-type littermates. Over time this effect was more pronounced in female mice that were also leaner than their wild-type counterparts, regardless of the diet. Decreased intake of a high-fat diet contributed to the attenuated weight gain in RIIαKO mice. Additionally, RIIα deficiency caused differential regulation of PKA in key metabolic organs: cAMP-stimulated PKA activity was decreased in liver and increased in gonadal adipose tissue. We conclude that RIIα represents a potential target for therapeutic interventions in obesity, glucose intolerance, and nonalcoholic fatty liver disease.
authors.affiliation: Section on Endocrinology and Genetics (E.L., M.N., E.S., S.A.M., C.A.S.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Biostatistics and Clinical Epidemiology Service (N.S.), CC, National Institutes of Health, Mouse Metabolism Core Laboratory (T.C., O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural Summer Student Program (S.A.M.), Bethesda, Maryland 20892.
authors.forename: Edra
authors.initials: E
authors.lastname: London
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chanturiya
authors.forename: Spyridon A
authors.initials: SA
authors.lastname: Mastroyannis
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000172:deficiency* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D018149:Glucose Intolerance / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*
chemical_list: D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases