O-GlcNAc,a monosaccharide derived from glucose,cycles on and off thousands of nucleocytoplasmic proteins and has extensive crosstalk with protein phosphorylation.Recent data shows that O-GlcNAc occurs on nearly all proteins involved in transcription,where it serves to regulate gene expression in response to nutrients.O-GlcNAc not only regulates assembly of the pre-initiation complex and the activity of RNA polymerase Ⅱ,but also the sugar regulates the cycling of the TATA-binding(TBP)protein on and off DNA during the transcription cycle.In vitro studies have also shown that O-GlcNAcylation of TBP is required for its ability to bend DNA,to mark sites of transcription initiation.Targeted,inducible,deletion of the O-GlcNAcTransferase in α CAMKⅡ positive(excitatory)neurons of adult mice results in a morbidly obese mouse,which cannot stop eating.Thus,O-GlcNAcylation not only serves as a nutrient sensor in all cells,but also is directly involved in appetite regulation(satiety)in select neurons in the brain.Recent studies have shown that more than one-half of all human protein kinases are modified by O-GlcNAc and all kinases that have been tested are indeed regulated in some way by the sugar.The fundamental involvement of O-GlcNAcylation in signaling and transcription explains why when O-GlcNAc is elevated for extended periods of time,as it is in diabetes,it contributes directly to diabetic complications and is a major mechanism of glucose toxicity.Supported by NIH P01HL107153,R01DK61671 and N01-HV-00240.