Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes

Akimoto, Yoshihiro; Kreppel, Lisa K.; Honda, Hiroshi; Hart, Gerald W.

doi:10.1007/s001250051519

Cited by 49 publications

(30 citation statements)

References 23 publications

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“…The overexpression of OGA had no significant effect on mitochondrial activity and myogenesis, with the exception of a dramatic decrease in O-GlcNAcylation. These data suggest that in addition to being closely involved in chronic diseases such as obesity, diabetes, neurodegeneration and cancer [8,9], OGA is also required to maintain normal mitochondrial function during myogenesis. Further studies are called for to explore the specific regulators involved in myogenesis that are modulated by OGA.…”

Section: Discussionmentioning

confidence: 92%

“…Aberrant O-GlcNAc signalling has been observed in a study of several chronic diseases, including obesity, diabetes, neurodegeneration and cancer [8,9]. In the study of diabetes, streptozotocin (STZ) has been used to induce a type 1 diabetic animal model by damaging pancreatic beta cells, resulting in hypoinsulinaemia and hyperglycaemia, while chronic high-caloric or high-fat diets (HFD) are usually used to induce type 2 diabetic animal models that are closely associated with obesity and insulin resistance; previous studies have revealed increased protein O-GlcNAcylation modification in both of these diabetic animal models [10][11][12][13], whereas exercise training has been shown to mitigate aberrant protein O-GlcNAcylation in diabetic mice [13].…”

Section: Introductionmentioning

confidence: 99%

“…Disruption of the OGT/OGA balance results in aberrant protein O-GlcNAc modification that contributes to physiological changes. A number of studies have demonstrated that increased OGT protein can contribute to insulin resistance [9,14,19]. Although the role of OGA in O-GlcNAc modification is known, the involvement of OGA in other biological processes remains limited.…”

Section: Introductionmentioning

confidence: 99%

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O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

et al. 2016

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Aims/hypothesis O-GlcNAcylation is implicated in modulating mitochondrial function, which is closely involved in regulating muscle metabolism. The presence of O-GlcNAcase (OGA), the enzyme involved in the removal of O-GlcNAc, in mitochondria was recently confirmed in rats. In the present study, we investigated the regulation of myogenesis and muscle insulin sensitivity to OGA in mice, with a focus on mitochondria. Methods C57BL/6J mice fed a high-fat diet for 4 months were used to observe mitochondrial density, activity and O-GlcNAcylation in muscle. Small interfering RNA and overexpression vectors were used to modulate protein content in vitro. Results High-fat feeding decreased the OGA level and largely increased mitochondrial O-GlcNAcylation in mouse skeletal muscle that was accompanied by decreased levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), decreased mitochondrial density and disrupted mitochondrial complex activities. Knockdown of OGA in C2C12 myoblasts promoted PGC-1α degradation, resulting in the suppression of mitochondrial biogenesis and myogenesis, whereas neither knockdown of O-GlcNAc transferase nor overexpression of OGA had significant effects on myogenesis. Mitochondrial dysfunction as evidenced by decreased ATP content and increased reactive oxygen species production, and increased lipid and protein oxidation was observed in both myoblasts and myotubes after OGA knockdown. Meanwhile, elevated O-GlcNAcylation through either OGA knockdown or treatment with the OGA inhibitor PUGNAc and the O-GlcNAc transferase substrate D-GlcNAc suppressed myotube insulin signalling transduction and glucose uptake. OGA overexpression had no significant effect on insulin sensitivity but sufficiently improved the insulin resistance induced by D-GlcNAc treatment. Conclusions/interpretation These data suggest that OGA can modulate mitochondrial density via PGC-1α and mitochondrial function via protein O-GlcNAcylation. In this manner, OGA appears to play a key role in myogenesis and the development of muscle insulin resistance.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

et al. 2016

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“…Streptozotocin, a structural analog of glucosamine, selectively destroys the ␤-cells of the pancreas and induces diabetes in a single relatively small dose (50 mg/kg of body weight). Streptozotocin is a weak inhibitor of O-GlcNAcase and elevates O-GlcNAc levels in the pancreas (62)(63)(64), suggesting that its mode of action may involve disruption of O-GlcNAc-mediated processes. Another recent study found that glucosamine may induce insulin resistance by preventing the transport of Glut4 vesicles from the cytoskeleton to the plasma membrane (65).…”

Section: Potential Implications Of ␤-O-glcnacmentioning

confidence: 99%

O-Glycosylation of Nuclear and Cytosolic Proteins

Comer

Hart

2000

Journal of Biological Chemistry

328

148

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“…One of the striking features of type 2 diabetes mellitus is insulin resistance. Resistance to insulin is associated with increased flux through the hexosamine biosynthetic pathway (28)(29)(30)(31)(32)(33) as well as with inhibition of OGA (34)(35)(36)(37)(38)(39)(40)(41)(42). The link between hexosamine signaling and human diabetes mellitus was more directly shown by the finding that a single nucleotide polymorphism in the MGEA5 gene encoding OGA is associated with diabetes mellitus and age of onset in the Mexican-American population (43).…”

mentioning

confidence: 99%

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

Forsythe

Love²,

Lazarus³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

147

206

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A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven ''hexosamine-signaling pathway.'' A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates OGlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser-and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3␤ (GSK-3␤) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C. elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling ''finetune'' insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C. elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.hexosamine ͉ insulin signaling ͉ nutrients ͉ obesity O -linked N-acetylglucosamine (O-GlcNAc) is a dynamic modification of nuclear pore complexes, transcription complexes, and kinases (1-4). Because of the diverse targets modified by O-GlcNAc, deciphering its role in cell physiology has proven challenging. Two enzymes regulate the cycling of O-GlcNAc: the O-linked GlcNAc transferase (OGT) and the glycosidase, OGlcNAcase (OGA) (1-4). In mammals, the two enzymes of OGlcNAc cycling are products of single genes; alternative splicing produces isoforms differing in subcellular location and substrate specificity (1,(5)(6)(7)(8)(9). The O-GlcNAc cycling enzymes act like kinases and phosphatases to modify Ser and Thr residues of target proteins. In addition, the hexosamine biosynthetic pathway giving rise to the O-GlcNAc donor, UDP-GlcNAc, is highly regulated and responsive to nutrient availability (4,(10)(11)(12)(13)(14).OGA, originally identified as a meningioma auto antigen and termed MGEA5 (8), is a member of the family 84 glycoside hydrolase {Carbohydrate-Active Enzymes [CAZy] database [GH 84 (caz, a)]}. OGA is highly conserved in eukaryotic evolution from Drosophila melanogaster and Caenorhabditis elegans to rodents and man. In mammals, the MGEA5 gene produces at least two isoforms differing ...

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Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes

Cited by 49 publications

References 23 publications

O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

O-GlcNAcase deficiency suppresses skeletal myogenesis and insulin sensitivity in mice through the modulation of mitochondrial homeostasis

O-Glycosylation of Nuclear and Cytosolic Proteins

Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 ( O -GlcNAcase) knockout impacts O -GlcNAc cycling, metabolism, and dauer

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