Metabolic Regulation by the Hexosamine Biosynthesis/O-Linked N-Acetyl Glucosamine Pathway

McClain, Donald A.; Taylor, Rodrick P.; Soesanto, Yudi; Luo, Bin

doi:10.2174/157436210790226474

Cited by 1 publication

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since we found that the expression of these proteins was similarly regulated by both classical insulin resistance and by solely raising global O-GlcNAc levels, we hypothesized that O-GlcNAc was a regulator. O-GlcNAc has been proposed to be a “nutrient sensor” because the levels of the end product of the HBP, UDP-GlcNAc, are regulated by the flux of glucose, uridine, glutamine, and FFA’s ( 93 , 94 ). OGT is responsive to physiological levels of UDP-GlcNAc, so increased HBP flux results in globally elevated levels of O-GlcNAc modification ( 95 ).…”

Section: Discussionmentioning

confidence: 99%

Global O-GlcNAc Levels Modulate Transcription of the Adipocyte Secretome during Chronic Insulin Resistance

et al. 2015

View full text Add to dashboard Cite

Increased flux through the hexosamine biosynthetic pathway and the corresponding increase in intracellular glycosylation of proteins via O-linked β-N-acetylglucosamine (O-GlcNAc) is sufficient to induce insulin resistance (IR) in multiple systems. Previously, our group used shotgun proteomics to identify multiple rodent adipocytokines and secreted proteins whose levels are modulated upon the induction of IR by indirectly and directly modulating O-GlcNAc levels. We have validated the relative levels of several of these factors using immunoblotting. Since adipocytokines levels are regulated primarily at the level of transcription and O-GlcNAc alters the function of many transcription factors, we hypothesized that elevated O-GlcNAc levels on key transcription factors are modulating secreted protein expression. Here, we show that upon the elevation of O-GlcNAc levels and the induction of IR in mature 3T3-F442a adipocytes, the transcript levels of multiple secreted proteins reflect the modulation observed at the protein level. We validate the transcript levels in male mouse models of diabetes. Using inguinal fat pads from the severely IR db/db mouse model and the mildly IR diet-induced mouse model, we have confirmed that the secreted proteins regulated by O-GlcNAc modulation in cell culture are likewise modulated in the whole animal upon a shift to IR. By comparing the promoters of similarly regulated genes, we determine that Sp1 is a common cis-acting element. Furthermore, we show that the LPL and SPARC promoters are enriched for Sp1 and O-GlcNAc modified proteins during insulin resistance in adipocytes. Thus, the O-GlcNAc modification of proteins bound to promoters, including Sp1, is linked to adipocytokine transcription during insulin resistance.

show abstract

Section: Discussionmentioning

confidence: 99%