Systemic immunometabolism

Helminth-derived molecules and insulin sensitivity: from immunomodulatory properties to direct regulation of metabolic tissues

Obesity, insulin resistance and type 2 diabetes are rising at an alarming rate and innovative therapeutic strategies are therefore needed for fighting against these metabolic diseases. Over the past year, it has been shown that type-2 immunity is crucial for maintenance of metabolic homeostasis. Interestingly, chronic helminth infection is known to trigger a potent Th2 immune response together with T-cell hyporesponsiveness through induction of a regulatory network, which have been both suggested to dampen meta-inflammation and restore tissue-specific and whole-body insulin sensitivity in both humans and obese mice. We have also shown that a mixture of molecules from helminth eggs - which mostly contains glycoproteins - could also improve insulin sensitivity, indicating that some glycosylated proteins might constitute a source of unique molecules for manipulating metabolic processes, either by triggering tissue-specific Th2 immune responses and/or by directly targeting metabolic cells via glycan-mediated interaction with specific receptors. Owing to our unique schistosome life cycle and associated growing portfolio of native and recombinant helminth glycoproteins, the overall objective of this research line is to study the immune-dependent and/or -independent mechanism(s) by which helminth infection and/or treatment with helminth-derived molecules could improve obesity-associated insulin resistance and restore glucose/lipid homeostasis.

Role of protein glycosylation in adipocyte-macrophage crosstalk during obesity

Obesity induces adipose tissue inflammation, which contributes to insulin resistance and progression towards type 2 diabetes.  The crosstalk between adipocytes and macrophages within fat tissue is central in this process but remains incompletely understood. Protein glycosylation is the reaction in which complex carbohydrate structures - called glycans - are attached to protein or lipids, 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/lipid glycans affect intercellular communication though interaction with carbohydrate-binding receptors (CBRs). Defects in glycosylation or alterations in protein/lipid 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 type 2 diabetes.

In the framework of this project, we are investigating the role played by adipocyte glycans and macrophage CBRs in the immune-dependent regulation of adipose tissue insulin sensitivity. For this purpose, state-of-the-art approaches combining (bio)chemical and genetic tools, in vitro co-culture system of human metabolic/immune cells, and unique mouse models are used.