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

• Published in: The Journal of clinical investigation Vol. 116; no. 12; pp. 3240 - 3251
• Main Authors: Choi, Young Hun, Park, Sunhee, Hockman, Steven, Zmuda-Trzebiatowska, Emilia, Svennelid, Fredrik, Haluzik, Martin, Gavrilova, Oksana, Ahmad, Faiyaz, Pepin, Laurent, Napolitano, Maria, Taira, Masato, Sundler, Frank, Stenson Holst, Lena, Degerman, Eva, Manganiello, Vincent C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-12-2006
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - genetics; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adiponectin - metabolism; Animals; Basic Medicine; Biomedical research; Blotting, Western; Cardiovascular system; Catecholamines; Catecholamines - metabolism; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 3; Energy Metabolism - genetics; Energy Metabolism - physiology; Female; Glucagon; Glucose; Homeostasis; Homeostasis - genetics; Homeostasis - physiology; Immunohistochemistry; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Kinases; Lipolysis - genetics; Lipolysis - physiology; Liver; Liver - metabolism; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Medicine, Experimental; Medicinska och farmaceutiska grundvetenskaper; Metabolism; Mice; Mice, Knockout; Peptides; Phosphodiesterases; Phosphorylation; Physiology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - physiology; Time Factors; Triglycerides - metabolism; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci24867

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 beta 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 beta(3)-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.