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Role of protein glycosylation in macrophage-adipocyte crosstalk during obesity

Projectomschrijving

Afweercellen en vetcellen in gesprek

Een verstoorde communicatie tussen afweercellen en vetcellen kan meespelen bij het ontstaan van diabetes type 2. Hoe precies?

We weten dat ontstekingsprocessen in het lichaam voorafgaan aan het ontstaan van diabetes type 2. Maar hoe dat gebeurt, is nog niet helemaal duidelijk. Daarom is er onderzoek gedaan op celniveau.

Signalen naar koolhydraatketens

Cellen kunnen elkaar signalen geven via hun zogeheten 'koolhydraatketens'. Dr. Guigas (LUMC) ging samen met een onderzoeker uit New York onderzoeken wat de rol is van koolhydraatketens in de communicatie tussen vetcellen en afweercellen. Ze gingen kijken hoe verschillen in koolhydraatketens tot stand komen. Hierbij werden cellen uit gezond en ontstoken vetweefsel met elkaar vergeleken.

De onderzoekers wilden begrijpen hoe veranderingen in koolhydraatketens van cellen leiden tot de ontregelde communicatie tussen afweercellen en vetcellen. Deze kennis kan hen dan vertellen hoe ze de ontsteking van vetweefsel kunnen tegengaan, en daarmee ook de ontwikkeling van diabetes type 2.

Duidelijke verschillen

De resultaten laten duidelijke verschillen zien tussen de koolhydraatketens van vetcellen als gevolg van obesitas, maar het is nog niet geanalyseerd in macrofagen (type afweercellen). De volgende stappen van het onderzoek zullen dieper ingaan op de specifieke veranderingen in de koolhydraatketens, met name gericht op het effect van deze veranderingen op de communicatie tussen macrofagen en vetcellen, en op chronische ontsteking in het vetweefsel in de context van obesitas.

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Titel: Effects of obesity on the glycosylation machinery in macrophages and adipocytes
Auteur: Joost Lambooij

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Samenvatting van de aanvraag

In the Netherlands, almost 1 million people have type 2 diabetes (T2D), leading to associated heath care cost estimated to be >5 billion euros per year. While some drug treatments are currently available, new discoveries are still needed to better understand the pathophysiology of the disease and expand the therapeutic arsenal for improving patient’s health. Obesity is associated with adipose tissue (AT) inflammation, which is one of the major contributors to insulin resistance and progression towards T2D. The interaction and communication between immune cells, especially macrophages, and adipocytes within the AT are thought to play an important role in this process and is largely determined by complex carbohydrate structures, called glycans, located on their cell surface and/or secretory proteins. Protein glycosylation is the reaction in which a glycan is attached to protein, especially on asparagine residues (N-glycosylation), and is one of the most common cellular process. Glycan composition and diversity is mainly determined by the activities of various components of the glycosylation machinery, especially by glycosyltransferases which are specific enzymes principally located in the Golgi apparatus. Changes in cell surface and/or secretory protein N-glycosylation affect intercellular communication though interaction with carbohydrate-binding receptors. Defects in glycosylation or alterations in protein glycan structure composition have been associated with various chronic diseases, such as cancer and inflammatory autoimmune diseases, but have not been yet extensively studied in the context of obesity and T2D. The present project at the interface between various scientific fields (metabolism, immunology and glycobiology) is therefore aimed to advance our understanding on the role played by macrophage/adipocyte protein N-glycosylation in the immune-dependent regulation of adipose tissue insulin sensitivity. Our working hypothesis is that changes in N-glycosylation of cell surface and/or secretory proteins resulting from cell-specific alterations of the glycosylation machinery during the course of obesity would affect macrophage-adipocyte crosstalk and contribute to AT insulin resistance. Our main objectives will be 1.) to study the effect of acute and chronic high-fat diet feeding on gene expression of key players of the glycosylation machinery and carbohydrate-binding receptors in AT macrophages (ATMs) and adipocytes from mice, and 2.) to characterize the cell surface and secretory protein N-glycome in both cell types. For these purposes, state-of-the-art approaches using quantitative RNA deep sequencing and mass spectrometry based-glycomics technologies will be used. This proof-of-concept project will bring together a unique combination of expertise from three complementary partners and is expected to contribute to significant breakthroughs in the growing field of immunometabolism. It can also potentially promote field cross-fertilisation by encouraging a better integration of glycobiological concepts and methodologies in the scientific community working on metabolic disorders. Despite the pre-clinical nature of the project, a constant attention will be paid to rapid validation and translation of our findings in humans. For this purpose, an ongoing collaboration with the group of Dr. Nicolas Venteclef (Institut des Cordeliers, Paris, France) will allow us the get access to transcriptomics data in isolated ATMs from obese individuals for validating some of our mouse findings, and to eventually conduct cell-specific glycomics analysis in a subset of newly collected set of human samples in the future. Altogether, we expect that the knowledge generated in the framework of this explorative project can pave the way for further related studies, ultimately contributing to the development of new pharmacological therapies for metabolic syndrome and T2D.

Kenmerken

Projectnummer:
459001007
Looptijd: 100%
Looptijd: 100 %
2018
2021
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. B.G. Guigas
Verantwoordelijke organisatie:
Leiden University Medical Center