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 10

Effects of insulin on glucose uptake, lipogenesis, and activation of PKB in adipocytes from 3- to 3.

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Effects of insulin on glucose uptake, lipogenesis, and activation of PKB...
-month-old WT and Pde3b-KO mice. (A and B) Adipocytes (0.2 ml 15% cells [vol/vol] in A; 1 ml 2.0% cells [vol/vol] in B) were incubated with the indicated concentrations of insulin for 10 minutes (A; n = 3) and 3 hours (B; n = 5). Uptake of 2-[1-3H]-deoxyglucose (A) and incorporation of D-[3H]-glucose into lipids (B) were measured as described in Methods and expressed as fold increase relative to nonstimulated cells. In KO adipocytes, basal lipogenesis was 56% ± 0.08% (mean ± SEM; P = 0.0001) that of WT adipocytes. Data (mean ± SEM) are from 5 independent experiments, each of which used adipocytes pooled from 2–3 mice. *P < 0.05; **P < 0.01. (C) Western blot analysis of FAS from WT and KO mice (20 μg protein/lane; n = 3) using anti-FAS antibody. (D) Adipocytes (each batch consisted of adipocytes from 2 of a total 6 WT and 6 KO mice) were incubated for 10 minutes with or without 1 nM insulin. Adipocyte fractions, prepared as described in Methods, were subjected to Western blotting with antibody recognizing PKB phosphorylated on serine 473 and, after stripping, with anti-PKB antibody. One Western blot representative of 3 is shown. PKB/phosphorylated PKB bands from 6 WT and 6 KO mice were quantified.