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

Valentina L Greto,Ana Cindrić,Niall J Dempster,Gordan Lauc,Tim D Spector,Richard S Gillies,Mario Falchi,Carolina V Arancibia-Cárcamo,Helena Deriš,Cristina Menni,Alessandra Geremia,Domagoj Kifer,Ana Cvetko,Frano Vučković,Bruno Sgromo,Olga Gornik,Tamara Štambuk,Jeremy W Tomlinson

doi:10.1038/s41366-021-00816-3

Abstract

BackgroundObesity, 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.MethodsIgG 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.ResultsLow-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).ConclusionsAltogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced glycan and biological age.

Highlights

The global prevalence of obesity has risen dramatically in the past decades, and it is a pandemic [1]
We investigated body mass index (BMI)-related N-glycosylation changes in the longitudinal TwinsUK cohort, the largest cohort of adult twins with the most detailed clinical database in the world
Since only plasma Nglycoprofile data was available for the TwinsUK cohort, the extrapolation of the IgG N-glycoprofile from plasma Nglycoprofile had to be performed as this was the only way to deduce IgG N-glycosylation information from the available

Summary

Introduction

The global prevalence of obesity has risen dramatically in the past decades, and it is a pandemic [1]. Metabolic syndrome is linked to a chronic systemic and tissue low-grade inflammation This long-term inflammatory state, known as inflammageing, accelerates the biological ageing process and exposes the organism to pathologies by weakening the immune system [3, 4]. We have investigated whether weight loss interventions affect inflammation- and ageing-associated IgG glycosylation changes, in a longitudinal cohort of bariatric surgery patients. This IgG N-glycan profile is known to be associated with a younger biological age and reflects an enhanced anti-inflammatory IgG potential. Conclusions Altogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced glycan and biological age

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