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 3

Gonadal fat weight, adipocyte diameters, and liver TG and FAS content in WT and Pde3b-KO mice.

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Gonadal fat weight, adipocyte diameters, and liver TG and FAS content in...
(A) WT and KO mice, housed 2 per cage and with free access to food and water, were fed normal chow. Caloric contents were 10%, 20%, and 70% fat, protein, and carbohydrate, respectively. For weight measurements, gonadal fat pads were collected from 6-month-old WT and KO mice (n = 6–8 mice per group). Data (mean ± SEM) were similar in 2 other experiments. (B and C) Diameter of epididymal adipocytes from age-matched 5-month-old WT and KO mice. (B) Cell diameter. Values are mean ± SEM (n = 357 WT and 447 KO cells). (C) Diameter distribution. The numbers of adipocytes with 5-μm intervals in their diameters were counted and plotted. Results are representative of 4 experiments. (D) Liver TG and FAS content. Liver TG content of 3- to 3.5-month-old male WT and KO mice was measured as described in Methods. Values are mean ± SEM (n = 18 per group). FAS content was determined by Western blot of liver homogenates (45 μg protein/lane) from WT and KO mice. Immunodetection was performed with anti-FAS antibody, and FAS bands were quantified. Values are mean ± SEM (n = 3 per group). *P < 0.05; **P < 0.01.