Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice.
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.
Choi
Young Hun
YH
Pulmonary-Critical Care Medicine Branch, NIH, Bethesda, MD 20892, USA. Choiy@nhlbi.nih.gov
Park
Sunhee
S
Hockman
Steven
S
Zmuda-Trzebiatowska
Emilia
E
Svennelid
Fredrik
F
Haluzik
Martin
M
Gavrilova
Oksana
O
Ahmad
Faiyaz
F
Pepin
Laurent
L
Napolitano
Maria
M
Taira
Masato
M
Sundler
Frank
F
Stenson Holst
Lena
L
Degerman
Eva
E
Manganiello
Vincent C
VC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics* / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002395:Catecholamines / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; D002395:Catecholamines; D007328:Insulin; D014280:Triglycerides; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse