Transgenic expression of a mutated cyclin-dependent kinase 4 (CDK4/R24C) in pancreatic beta-cells prevents progression of diabetes in db/db mice.
In an attempt to rectify the hyperglycemic state in obese insulin resistant db/db mice, a transgenic line was generated (db/db-CDK4(R24C)) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/db littermates, adult db/db-CDK4(R24C) mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and beta-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/db-CDK4(R24C) as well as db/db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor (PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-delta in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/db mice. The db/db-CDK4(R24C) mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.
Miyawaki
Katsuyuki
K
Division of Genetic Information, Institute for Genome Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima, Tokushima 770-8503, Japan.
Inoue
Hiroshi
H
Keshavarz
Parvaneh
P
Mizuta
Kuniko
K
Sato
Aya
A
Sakamoto
Yukiko
Y
Moritani
Maki
M
Kunika
Kiyoshi
K
Tanahashi
Toshihito
T
Itakura
Mitsuo
M
D052242:Adiponectin / Q000097:blood; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D052242:Adiponectin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; D008055:Lipids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; D051358:Cyclin-Dependent Kinase 4