TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway

Elevated plasma angiotensinogen (AGT) levels have been demonstrated in insulin-resistant states such as obesity and type 2 diabetes mellitus (DM2), conditions that are directly correlated to hypertension. We examined whether hyperinsulinemia or hyperglycemia may modulate fat and liver AGT gene expression and whether obesity and insulin resistance are associated with abnormal AGT regulation. In addition, because the hexosamine biosynthetic pathway is considered to function as a biochemical sensor of intracellular nutrient availability, we hypothesized that activation of this pathway would acutely mediate in vivo the induction of AGT gene expression in fat and liver. We studied chronically catheterized lean (∼300 g) and obese (∼450 g) Sprague-Dawley rats in four clamp studies ( n= 3/group), creating physiological hyperinsulinemia (∼60 μU/ml, by an insulin clamp), hyperglycemia (∼18 mM, by a pancreatic clamp using somatostatin to prevent endogenous insulin secretion), or euglycemia with glucosamine infusion (GlcN; 30 μmol · kg−1 · min−1) and equivalent saline infusions (as a control). Although insulin infusion suppressed AGT gene expression in fat and liver of lean rats, the obese rats demonstrated resistance to this effect of insulin. In contrast, hyperglycemia at basal insulin levels activated AGT gene expression in fat and liver by approximately threefold in both lean and obese rats ( P < 0.001). Finally, GlcN infusion simulated the effects of hyperglycemia on fat and liver AGT gene expression (2-fold increase, P < 0.001). Our results support the hypothesis that physiological nutrient “pulses” may acutely induce AGT gene expression in both adipose tissue and liver through the activation of the hexosamine biosynthetic pathway. Resistance to the suppressive effect of insulin on AGT expression in obese rats may potentiate the effect of nutrients on AGT gene expression. We propose that increased AGT gene expression and possibly its production may provide another link between obesity/insulin resistance and hypertension.

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The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance

Acta Physiologica ◽

10.1111/j.1748-1716.2011.02275.x ◽

2011 ◽

Vol 202 (2) ◽

pp. 151-157 ◽

Cited By ~ 10

Author(s):

U. Rajamani ◽

D. Joseph ◽

S. Roux ◽

M. F. Essop

Keyword(s):

Insulin Resistance ◽

Rat Model ◽

Biosynthetic Pathway ◽

Hexosamine Biosynthetic Pathway ◽

Myocardial Apoptosis

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Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells

Molecular and Cellular Biochemistry ◽

10.1007/s11010-009-0092-7 ◽

2009 ◽

Vol 328 (1-2) ◽

pp. 217-224 ◽

Cited By ~ 25

Author(s):

V. Srinivasan ◽

U. Tatu ◽

V. Mohan ◽

M. Balasubramanyam

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Er Stress ◽

Biosynthetic Pathway ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Hexosamine Biosynthetic Pathway ◽

L6 Skeletal Muscle Cells ◽

Molecular Convergence

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233: Hexosamine biosynthetic pathway: does it contribute to insulin resistance of pregnancy?

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2009.10.248 ◽

2009 ◽

Vol 201 (6) ◽

pp. S97

Author(s):

Hye Heo ◽

Roopali Donepudi ◽

Reshmi Madankumar ◽

Derek M. Huffman ◽

Radhika Muzumdar ◽

...

Keyword(s):

Insulin Resistance ◽

Biosynthetic Pathway ◽

Hexosamine Biosynthetic Pathway

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High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

International Journal of Molecular Sciences ◽

10.3390/ijms22073746 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3746

Author(s):

Ilaria Zuliani ◽

Chiara Lanzillotta ◽

Antonella Tramutola ◽

Eugenio Barone ◽

Marzia Perluigi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

High Fat Diet ◽

Mitochondrial Activity ◽

High Fat ◽

Hexosamine Biosynthetic Pathway ◽

Neurodegenerative Process ◽

The Brain

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process.

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The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model

International Journal of Molecular Sciences ◽

10.3390/ijms22147247 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7247

Author(s):

Jana Riegger ◽

Julia Baumert ◽

Frank Zaucke ◽

Rolf E. Brenner

Keyword(s):

Biosynthetic Pathway ◽

Ex Vivo ◽

Type Ii Collagen ◽

Cartilage Explants ◽

Uridine Diphosphate ◽

Cell Protection ◽

Ex Vivo Model ◽

Human Cartilage ◽

Hexosamine Biosynthetic Pathway ◽

Cellular Processes

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

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