The Krüppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4.
Resistance to the stimulatory effects of insulin on glucose utilization is a key feature of type 2 diabetes, obesity, and the metabolic syndrome. Recent studies suggest that insulin resistance is primarily caused by a defect in glucose transport. GLUT4 is the main insulin-responsive glucose transporter and is expressed predominantly in muscle and adipose tissues. Whereas GLUT4 has been shown to play a critical role in maintaining systemic glucose homeostasis, the mechanisms regulating its expression are incompletely understood. We have cloned the murine homologue of KLF15, a member of the Krüppel-like family of transcription factors. KLF15 is highly expressed in adipocytes and myocytes in vivo and is induced when 3T3-L1 preadipocytes are differentiated into adipocytes. Overexpression of KLF15 in adipose and muscle cell lines potently induces GLUT4 expression. This effect is specific to KLF15 as overexpression of two other Krüppel-like factors, KLF2/LKLF and KLF4/GKLF, did not induce GLUT4 expression. Both basal (3.3-fold, p < 0.001) and insulin-stimulated (2.4-fold, p < 0.00001) glucose uptake are increased in KLF15-overexpressing adipocytes. In co-transfection assays, KLF15 and MEF2A, a known activator of GLUT4, synergistically activates the GLUT4 promoter. Promoter deletion and mutational analyses provide evidence that this activity requires an intact KLF15-binding site proximal to the MEF2A site. Finally, co-immunoprecipitation assays show that KLF15 specifically interacts with MEF2A. These studies indicate that KLF15 is an important regulator of GLUT4 in both adipose and muscle tissues.
Gray
Susan
S
Cardiovascular Division, Brigham and Women's Hospital, Thorn Building, 20 Shattuck Street, Boston, MA 02115, USA.
Feinberg
Mark W
MW
Hull
Sarah
S
Kuo
Chay T
CT
Watanabe
Masafumi
M
Sen-Banerjee
Sucharita
S
DePina
Ana
A
Haspel
Richard
R
Jain
Mukesh K
MK
D016475:3T3 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D015533:Transcriptional Activation
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; C467418:Klf15 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D004247:DNA; D005947:Glucose