Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension

Abstract

Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. Methods: Involvement of IgG was studied using IgG μ heavy chain–null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell–specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow–fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

Interferon-α alters host glycosylation machinery during treated HIV infection

“…Soluble CD14 negatively impacts CD8 + T cells activation and function by directly interacting with T cells [40] . The robust literature on the direct impact of IgG glycomic alterations (including bisecting glycans) on inflammation [16 , 32 , 34 , [65] , [66] , [67] , [68] , [69] , supports our model in which IFNα increases the proportion of pro-inflammatory, bisecting GlcNAc glycans in the IgG glycome, which in turn increases levels of monocyte/macrophage inflammation/activation, leading to poor CD8 + T functions. This model warrants further investigation as it may help explain some of the detrimental impact of IFNα on host immune functions, especially given the known link between sCD14/sCD163 levels and both mortality and morbidity during chronic HIV infection [70 , 71] .…”

“…This model warrants further investigation as it may help explain some of the detrimental impact of IFNα on host immune functions, especially given the known link between sCD14/sCD163 levels and both mortality and morbidity during chronic HIV infection [70 , 71] . While IgG glycomic dysregulations can induce inflammation directly [16 , 32 , 34 , [65] , [66] , [67] , [68] , [69] , IFNs are known to induce hundreds of interferon-stimulated genes (ISGs) and modulate the production of other cytokines. Therefore, future studies will be needed to investigate the direct versus indirect consequences of IFNα on the host glycosylation machinery as well as on monocyte/macrophage inflammatory and glycomic interactions.…”

Glycocalyx sialic acids regulate Nrf2-mediated signaling by fluid shear stress in human endothelial cells

“…Microvascular dysfunction has also been linked to age-related GCX decline [ 97 ], therefore therapeutic strategies that mitigate GCX deterioration are likely to reduce the risk and severity of CVD in ageing [ 98 ]. Notably, experimental restoration of SIA has been shown to be efficacious against atherosclerosis [ 99 ], obesity-related hypertension [ 100 ] and age-related renal microvascular dysfunction [ 101 ]. Furthermore, it was recently reported that GCX enhancement by the GAG supplement sulodexide activates Nrf2 signaling to confer cytoprotection against ischaemia-reperfusion injury [ 102 ].…”

Extensive weight loss can reduce immune age by altering IgG N-glycosylation

“…On the other hand, the sialylated glycoform is not activating the signalling pathways responsible for the insulin resistance and hypertension development, but is rather preserving insulin sensitivity and normal vasomotor tone, even in obese mice. Interestingly, the same group made another significant discovery – promotion of IgG sialylation breaks the link between obesity and hypertension/insulin resistance [21,22]. Namely, supplementation with the sialic acid precursor restored IgG sialylation, highlighting a potential approach to improve both metabolic and cardiovascular health in humans, with a single intervention.…”

“…These findings indicate that the IgG N-glycome could represent more than a biomarker of inflammation and aging, since distinctive IgG glycoforms act as effector molecules in certain pathologies. Furthermore, supplementation with N -acetylmannosamine (ManNAc), a precursor of sialic acid, protects obese mice from hypertension and insulin resistance induction by reverting an IgG N-glycome associated with old age into an IgG N-glycome associated with young age [21,22]. However, studies exploring the possibilities of converting an old-like into a young-like IgG glycome by metabolic intervention in humans are limited.…”