A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout.
O-linked N-acetylglucosamine (O-GlcNAc) is an evolutionarily conserved modification of nuclear pore proteins, signaling kinases, and transcription factors. The O-GlcNAc transferase (OGT) catalyzing O-GlcNAc addition is essential in mammals and mediates the last step in a nutrient-sensing "hexosamine-signaling pathway." This pathway may be deregulated in diabetes and neurodegenerative disease. To examine the function of O-GlcNAc in a genetically amenable organism, we describe a putative null allele of OGT in Caenorhabditis elegans that is viable and fertile. We demonstrate that, whereas nuclear pore proteins of the homozygous deletion strain are devoid of O-GlcNAc, nuclear transport of transcription factors appears normal. However, the OGT mutant exhibits striking metabolic changes manifested in a approximately 3-fold elevation in trehalose levels and glycogen stores with a concomitant approximately 3-fold decrease in triglycerides levels. In nematodes, a highly conserved insulin-like signaling cascade regulates macronutrient storage, longevity, and dauer formation. The OGT knockout suppresses dauer larvae formation induced by a temperature-sensitive allele of the insulin-like receptor gene daf-2. Our findings demonstrate that OGT modulates macronutrient storage and dauer formation in C. elegans, providing a unique genetic model for examining the role of O-GlcNAc in cellular signaling and insulin resistance.
Hanover
John A
JA
Laboratories of Cell Biochemistry and Biology and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jah@helix.nih.gov
Forsythe
Michele E
ME
Hennessey
Patrick T
PT
Brodigan
Thomas M
TM
Love
Dona C
DC
Ashwell
Gilbert
G
Krause
Michael
M
D000818:Animals; D017173:Caenorhabditis elegans; D002329:Carmine / Q000031:analogs & derivatives; D017931:DNA Primers; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006003:Glycogen / Q000378:metabolism; D015151:Immunoblotting; D007333:Insulin Resistance / Q000235:genetics*; D007814:Larva / Q000254:growth & development; D009154:Mutation / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010078:Oxazines; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014199:Trehalose / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D017931:DNA Primers; D010078:Oxazines; D014280:Triglycerides; D006003:Glycogen; D014199:Trehalose; D002329:Carmine; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C044808:nile red