Extensive weight loss reduces glycan age by altering IgG N-glycosylation

Abstract

Background: Obesity, a major global health problem, is associated with increased cardiometabolic morbidity and mortality. Protein glycosylation is a frequent posttranslational modification, highly responsive to inflammation and ageing. The prospect of biological age reduction, by changing glycosylation patterns through metabolic intervention, opens many possibilities. We have investigated whether weight loss interventions affect inflammation- and ageing-associated IgG glycosylation changes, in a longitudinal cohort of bariatric surgery patients. To support potential findings, BMI-related glycosylation changes were monitored in a longitudinal twins cohort.

Methods: IgG N-glycans were chromatographically profiled in 37 obese patients, subjected to low-calorie diet, followed by bariatric surgery, across multiple timepoints. Similarly, plasma-derived IgG N-glycan traits were longitudinally monitored in 1680 participants from the TwinsUK cohort.

Results: Low-calorie diet induced a marked decrease in the levels of IgG N-glycans with bisecting GlcNAc, whose higher levels are usually associated with ageing and inflammatory conditions. Bariatric surgery resulted in extensive alterations of the IgG N-glycome that accompanied progressive weight loss during 1-year follow-up. We observed a significant increase in digalactosylated and sialylated glycans, and a substantial decrease in agalactosylated and core fucosylated IgG N-glycans (adjusted p value range 7.38 × 10^-04-3.94 × 10^-02). This IgG N-glycan profile is known to be associated with a younger biological age and reflects an enhanced anti-inflammatory IgG potential. Loss of BMI over a 20 year period in the TwinsUK cohort validated a weight loss-associated agalactosylation decrease (adjusted p value 1.79 × 10^-02) and an increase in digalactosylation (adjusted p value 5.85 × 10^-06).

Conclusions: Altogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced glycan and biological age.

Fig. 1. Bariatric surgery-related alterations in IgG N-glycosylation features over time (months).

Standardised glycan measurements are represented on the y-axis, while time in months is presented on the x-axis. IgG N-glycosylation altered features: G0 – agalactosylation; G1 – monogalactosylation; G2 – digalactosylation; S total – total sialylation; S1 – monosialylation; S2 – disialylation; CF – core fucosylation; B – incidence of bisecting N-acetylglucosamine. Red line – significant decrease; green line – significant increase; blue line – non-significant change.

Fig. 2. BMI-associated alterations in IgG N-glycosylation across multiple timepoints.

Changes in IgG N-glycosylation derived traits are presented with lineplots of hypothetical ageing of TwinsUK participants (all women). Black dot represents a starting point of a 30-year-old woman, black triangle of a 40-year-old woman and black square of a 50-year-old woman. All of these women have a baseline BMI of 25 kg/m². Blue lines represent age-related IgG N-glycosylation changes attributed to stabile BMI. Green lines represent age-related IgG N-glycosylation changes attributed to increasing BMI (0.5 kg/m² per year, through a period of 10 years). Red lines represent age-related IgG N-glycosylation changes attributed to decreasing BMI (0.5 kg/m² per year, through a period of 10 years). Highlighted areas represent 95% confidence intervals. The effect of age on IgG N-glycosylation is represented with the curve slope, while the effect of BMI change is represented with the distance of green/red line from the blue line.