Transcriptional regulation of the GLUT4 gene: from PPAR-gamma and FOXO1 to FFA and inflammation.
The insulin-responsive glucose transporter 4 (GLUT4) has a major role in glucose uptake and metabolism in insulin target tissues (i.e. adipose and muscle cells). In these tissues, the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors and the winged-helix-forkhead box class O (FOXO) family of factors are two key families of transcription factors that regulate glucose homeostasis and insulin responsiveness. Type 2 diabetes mellitus and obesity are associated with impaired regulation of GLUT4 gene expression and elevated levels of free fatty acids and proinflammatory factors. Based on our studies of the interplay between PPAR-gamma, FOXO1 and free fatty acids, and inflammation in regulating GLUT4 transcription in sickness and in health, we suggest a novel paradigm to increase insulin sensitivity in bona fide insulin target cells.
Armoni
Michal
M
Institute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
Harel
Chava
C
Karnieli
Eddy
E
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D006262:Health; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D005230:Fatty Acids, Nonesterified; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051275:Glucose Transporter Type 4; D047495:PPAR gamma