Adipocyte-specific reduction of phosphodiesterase 3B gene expression and its restoration by JTT-501 in the obese, diabetic KKAy mouse.
OBJECTIVE
Phosphodiesterase (PDE) 3B is a key enzyme involved in the anti-lipolytic action of insulin in adipocytes. PDE3B activation results in a reduced output of free fatty acids (FFA), whereas elevated serum FFA is known to cause insulin resistance. We have recently reported that reduced PDE3B gene expression is restored by treatment with pioglitazone, in the adipose tissues of obese, insulin-resistant diabetic KKAy mice. To determine whether the altered PDE3B gene expression is specific for adipocytes, the expression of this gene in liver and epididymal fat tissues of KKAy mice was examined. The effect of JTT-501, another peroxisome proliferator-activated receptor (PPAR)gamma ligand, which is different from thiazolidinedione, was also examined.


METHODS
PDE3B mRNA and protein were quantified by an RNase protection assay and Western blotting respectively. Membrane-bound PDE activities were also measured.


RESULTS
In adipose tissues of KKAy mice, PDE3B mRNA, protein and membrane-bound PDE activity were reduced to 47%, 57% and 51% respectively relative to those in C57BL/6J control mice. JTT-501 increased PDE3B mRNA, protein and membrane-bound PDE activity by 2.2-, 1.6- and 1.7-fold respectively over those of untreated KKAy mice. In the liver, PDE3B gene expression remained unchanged in KKAy mice, and was not affected by JTT-501. JTT-501 reduced the elevated levels of serum insulin, glucose, FFA and triglyceride in KKAy mice.


CONCLUSIONS
PDE3B gene expression was specifically reduced in the adipose tissues of KKAy mice. JTT-501 restored this reduced gene expression with an accompanying improvement in elevated serum FFA and insulin resistance.
Tang
Y
Y
Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan.
Osawa
H
H
Onuma
H
H
Hasegawa
M
M
Nishimiya
T
T
Ochi
M
M
Makino
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D003920:Diabetes Mellitus / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D004822:Epididymis / Q000187:drug effects / Q000201:enzymology; D005227:Fatty Acids / Q000097:blood; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D007555:Isoxazoles; D012333:RNA, Messenger; D014280:Triglycerides; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse; C112329:JTT 501