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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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 4

Effects of ISO, CL, and insulin on lipolysis in intact mice and adipocytes.

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Effects of ISO, CL, and insulin on lipolysis in intact mice and adipocyt...
(A and B) ISO or CL (1.0 mg/kg each) in PBS, or PBS alone, was injected i.p. (10 ml/kg) into 6-month-old WT and KO mice. After 20 minutes, serum glycerol (A) and FFA (B) levels were quantified. Values are mean ± SEM (n = 4 per group). Differences between serum glycerol or FFA concentrations after PBS alone (basal) and after drug administration are shown. Basal values in WT and KO mice were 20.5 ± 2.7 and 23.7 ± 1.2 mg/dl glycerol, respectively, and 1.49 ± 0.21 and 1.13 ± 0.25 mM FFA, respectively. Data were similar in 3 other experiments. (C and D) Adipocytes (0.4 ml, 5% [vol/vol]) prepared from epididymal fad pads of 6-month-old WT and KO mice were incubated for 60 minutes at 37°C in Krebs-Ringer–HEPES buffer alone or with the indicated concentrations of ISO, CL, or insulin (Ins). Lipolysis was measured as glycerol accumulation in the medium. Data are mean ± SEM of 3 incubations (duplicate assays). (C) Basal glycerol values were 0.13 ± 0.02 and 0.12 ± 0.01 nEq/h/103 cells for WT and KO, respectively. Data were similar in 3 other experiments. (D) Basal glycerol values were 0.24 ± 0.13 and 0.13 ± 0.08 nEq/h/103 cells for WT and KO, respectively. Data were similar in 2 other experiments. *P < 0.05; **P < 0.01.