London Edra, Nesterova Maria, Sinaii Ninet, Szarek Eva, Chanturiya Tatyana, Mastroyannis Spyridon A, Gavrilova Oksana, Stratakis Constantine A
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.
Endocrinology. 2014 Sep;155(9):3397-408. doi: 10.1210/en.2014-1122. Epub 2014 Jun 10.
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.
环磷酸腺苷（cAMP）依赖性蛋白激酶A（PKA）信号系统广泛表达，在调节受肥胖影响的所有器官系统的细胞代谢中起核心作用。PKA有四种调节亚基（RIα、RIIα、RIβ、RIIβ）和四种催化亚基（Cα、Cβ、Cγ、Prkx）亚型，它们具有组织特异性表达谱。在小鼠中，脂肪组织中的主要PKA调节亚基RIIβ敲除（KO）或催化亚基Cβ敲除会导致瘦型表型，抵抗饮食诱导的肥胖及相关代谢并发症。在此我们报告，小鼠中普遍表达的PKA RIIα亚基的破坏（RIIαKO）赋予了对饮食诱导的肥胖、葡萄糖不耐受和肝脂肪变性的抗性。经过2周的高脂饮食暴露后，RIIαKO小鼠的体重低于野生型同窝小鼠。随着时间的推移，这种效应在雌性小鼠中更为明显，无论饮食如何，雌性小鼠也比其野生型同窝小鼠更瘦。高脂饮食摄入量的减少导致RIIαKO小鼠体重增加减弱。此外，RIIα缺乏导致关键代谢器官中PKA的差异调节：环磷酸腺苷刺激的PKA活性在肝脏中降低，而在性腺脂肪组织中增加。我们得出结论，RIIα是肥胖、葡萄糖不耐受和非酒精性脂肪肝病治疗干预的潜在靶点。
