A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout

Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11266-71. doi: 10.1073/pnas.0408771102. Epub 2005 Jul 28.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Caenorhabditis elegans*
  • Carmine / analogs & derivatives
  • DNA Primers
  • Disease Models, Animal*
  • Fluorescent Antibody Technique
  • Glycogen / metabolism
  • Immunoblotting
  • Insulin Resistance / genetics*
  • Larva / growth & development
  • Mutation / genetics
  • N-Acetylglucosaminyltransferases / genetics*
  • Oxazines
  • Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Trehalose / metabolism
  • Triglycerides / metabolism

Substances

  • DNA Primers
  • Oxazines
  • Triglycerides
  • Glycogen
  • Trehalose
  • Carmine
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • nile red