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 8

Hepatic cAMP content and gluconeogenic gene expression in nonfasted and 6-hour-fasted WT and Pde3b-KO mice.

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Hepatic cAMP content and gluconeogenic gene expression in nonfasted and ...
(A) Hepatic cAMP content. cAMP was measured in liver extracts from 5-month-old WT and Pde3b-KO mice either fed or fasted for 6 hours as described in Methods. Values on the y axis represent nanomoles of cAMP per gram of liver. Data (mean ± SEM; n = 4 per group), which represent duplicate assays, were similar in a second group of fasted and nonfasted WT and KO mice. (B and C) Western blotting of liver lysates (50 μg protein/lane) was performed as described in Methods. n = 4 fed, 3 fasted mice per group. Data from a second, identical group of fed (n = 4) and 6-hour fasted (n = 3) WT and KO mice were similar. (B) Immunodetection with anti-PKA substrates antibody, which detects substrate proteins phosphorylated by cAMP-dependent protein kinase. (C) Immunodetection with anti–phospho-CREB (pS133); anti-CREB; anti–PGC-1α; anti-PEPCK; anti-TRB3; anti–SOCS-3; and anti-actin antibodies.