Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice
Young Hun Choi, … , Eva Degerman, Vincent C. Manganiello
Young Hun Choi, … , Eva Degerman, Vincent C. Manganiello
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3240-3251. https://doi.org/10.1172/JCI24867.
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Research Article Metabolism

Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice

Abstract

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 β 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 lipogenesis, 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 β3-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.

Authors

Young Hun Choi, Sunhee Park, Steven Hockman, Emilia Zmuda-Trzebiatowska, Fredrik Svennelid, Martin Haluzik, Oksana Gavrilova, Faiyaz Ahmad, Laurent Pepin, Maria Napolitano, Masato Taira, Frank Sundler, Lena Stenson Holst, Eva Degerman, Vincent C. Manganiello

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Figure 1

Targeted disruption of the murine Pde3b gene.

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Targeted disruption of the murine Pde3b gene. (A) Struct...
(A) Structure of the approximately 13-kb SalIPDE3B WT genomic fragment containing 5′-untranslated region and exon 1. (B) WT and disrupted KO gene fragments near exon 1. (C) Pde3b targeting vector. S, SalI; X, XbaI; B, BstXI; N, NotI; H, HindIII. (D) Southern blot of WT, HE, and KO genomic DNA, digested with BstXI and hybridized to 32P-labeled probe 0.4 (see A and C). (E) PCR amplification of WT, HE, and KO genomic DNA using the specific primers A, E, and R indicated in A and B (A and E for lane 1; A and R for lane 2). (F) RT-PCR amplification of mRNA from WT, HE, and KO livers with primers described in Methods targeted for PDE3A (lane 1), PDE3B (lane 2), and Neor (lane 3). M, molecular weight marker. (G) Quantitation of cyclophilin A (Cyc), PDE3A, and PDE3B mRNAs in WT, HE, and KO mouse livers by real-time RT-PCR. Data were normalized to the quantity of WT cyclophilin A mRNA, taken as 100 AU. Values represent mean ± SEM (n = 4 per genotype in triplicate assays). Data were similar in 2 other groups of WT and KO mice and 1 group of HE mice. **P < 0.01. (H and I) Northern blot of WT and KO mRNAs, using probe B for mPDE3B (fat pads and liver; H) or probe A for mPDE3A (heart; I) as described in Methods. M, male; F, female; W, WT mRNA; K, KO mRNA.