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The Role of O-GlcNAcylation in Perivascular Adipose Tissue Dysfunction of Offspring of High-Fat Diet-Fed Rats
Karolina E Zaborska1, Gillian Edwards, Clare Austin
1Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
Insights
Prenatal high-fat diet (HFD) exposure programs perivascular adipose tissue (PVAT) dysfunction in male offspring, linked to increased O-GlcNAcylation and reduced nitric oxide (NO) bioavailability. This dysfunction impairs PVAT
Area of Science:
- Endocrinology
- Vascular Biology
- Metabolic Syndrome
Background:
- Perivascular adipose tissue (PVAT) normally reduces vascular contractility.
- Maternal high-fat diet (HFD) during gestation and lactation leads to dysfunctional PVAT in male offspring.
- Reduced nitric oxide (NO) bioavailability contributes to PVAT dysfunction.
Purpose of the Study:
- To investigate the role of O-GlcNAcylation in the prenatal programming of PVAT dysfunction.
- To understand how maternal HFD affects PVAT function and molecular pathways in offspring.
Main Methods:
- Female rats fed control or HFD diets before and during pregnancy/lactation.
- Offspring assessed at 12 and 24 weeks for vascular contractility and PVAT function.
- O-GlcNAcylation, AMPK activity, and eNOS phosphorylation levels were analyzed.
Main Results:
- Offspring of HFD dams (HFDO) exhibited reduced vascular contractility and loss of PVAT anticontractile effect.
- Glucosamine mimicked HFD effects, suggesting O-GlcNAcylation involvement.
- AMPK activation partially restored anticontractile effects in HFDO PVAT.
- Glucosamine decreased AMPK activity and expression in HFDO PVAT, with reduced p-eNOS in males.
Conclusions:
- Prenatal HFD exposure causes PVAT dysfunction in male offspring, likely via increased O-GlcNAcylation.
- This dysfunction is associated with decreased AMPK activity and, in males, reduced NO bioavailability.
- O-GlcNAcylation emerges as a key mechanism in programming PVAT dysfunction by maternal HFD.
Abstract:
Perivascular adipose tissue (PVAT), which reduces vascular contractility, is dysfunctional in the male offspring of rats fed a high-fat diet (HFD), partially due to a reduced NO bioavailability. O-GlcNAcylation of eNOS decreases its activity, thus we investigated the role of O-GlcNAcylation in the prenatal programming of PVAT dysfunction. Female Sprague-Dawley rats were fed either a control (10% fat) or an obesogenic HFD (45% fat) diet for 12 weeks prior to mating, and throughout pregnancy and lactation. Offspring were weaned onto the control diet and were killed at 12 and 24 weeks of age. Mesenteric arteries from the 12-week-old offspring of HFD dams (HFDO) contracted less to U46619; these effects were mimicked by glucosamine in control arteries. PVAT from 12- and 24-week-old controls, but not from HFDO, exerted an anticontractile effect. Glucosamine attenuated the anticontractile effect of PVAT in the vessels from controls but not from HFDO. AMP-activated protein kinase (AMPK) activation (with A769662) partially restored an anticontractile effect in glucosamine-treated controls and HFDO PVAT. Glucosamine decreased AMPK activity and expression in HFDO PVAT, although phosphorylated eNOS expression was only reduced in that from males. The loss of anticontractile effect of HFDO PVAT is likely to result from increased O-GlcNAcylation, which decreased AMPK activity and, in males, decreased NO bioavailability.