Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice
Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice
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DOI：
10.1172/jci24867
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发表时间：
2006-12-01
影响因子：
15.9
通讯作者：
Manganiello, Vincent C.
中科院分区：
文献类型：
--
作者：
Choi, Young Hun;Park, Sunhee;Manganiello, Vincent C.
环核苷酸磷酸二酯酶3B(PDE3B)在介导胰岛素/IGF-1抑制脂肪细胞、肝脏和胰岛β细胞内cAMP信号转导中起关键作用。在Pde3b-KO脂肪细胞中，我们发现脂肪细胞体积减小，胰岛素刺激的蛋白激酶B的磷酸化和葡萄糖摄取的激活没有变化，儿茶酚胺刺激的脂肪分解和胰岛素刺激的生发作用增强，胰岛素抑制儿茶酚胺刺激的脂肪分解。单独使用葡萄糖或联合应用胰升糖素样肽-1可显著增加胰岛胰岛素的分泌，但胰岛的大小和形态以及胰岛素和胰升糖素免疫反应性水平没有变化。β(3)-肾上腺素能激动剂CL 316,243(CL)能增加KO小鼠的脂肪分解和血清胰岛素水平，但降低血糖的作用较小。在KO小鼠中观察到了胰岛素抵抗，肝脏是胰岛素敏感葡萄糖产生变化的重要部位。在KO小鼠中，肝脏甘油三酯和cAMP含量增加，肝脏内容物和几种胰岛素信号、糖异生、炎症和应激相关成分的磷酸化状态发生改变。因此，PDE3B可能在调节某些cAMP信号通路中起重要作用，包括脂解、胰岛素诱导的抗脂作用和cAMP介导的胰岛素分泌。PDE3B表达和/或调节的改变可能导致代谢失调，包括全身性胰岛素抵抗。
Cyclic nucleotide phosphodiesterase 3B (PDE3B) has been suggested to be critical for mediating insulin/IGF-1 inhibition of cAMP signaling in adipocytes, liver, and pancreatic beta cells. In Pde3b-KO adipocytes we found decreased adipocyte size, unchanged insulin-stimulated phosphorylation of protein kinase B and activation of glucose uptake, enhanced catecholamine-stimulated lipolysis and insulin-stimulated hpogenesis, and blocked insulin inhibition of catecholamine-stimulated lipolysis. Glucose, alone or in combination with glucagon-like peptide-1, increased insulin secretion more in isolated pancreatic KO islets, although islet size and morphology and immunoreactive insulin and glucagon levels were unchanged. The beta(3)-adrenergic agonist CL 316,243 (CL) increased lipolysis and serum insulin more in KO mice, but blood glucose reduction was less in CL-treated KO mice. Insulin resistance was observed in KO mice, with liver an important site of alterations in insulin-sensitive glucose production. In KO mice, liver triglyceride and cAMP contents were increased, and the liver content and phosphorylation states of several insulin signaling, gluconeogenic, and inflammation- and stress-related components were altered. Thus, PDE3B may be important in regulating certain cAMP signaling pathways, including lipolysis, insulin-induced antilipolysis, and cAMP-mediated insulin secretion. Altered expression and/or regulation of PDE3B may contribute to metabolic dysregulation, including systemic insulin resistance.