Type 2 Diabetes (T2D) is the main epidemic of this century. A recent hypothesis of medical research is that an important cause of T2D may be the abnormal regulation of glucose absorption in the small intestine. The objective of the present project is to investigate the relative contribution of each regulatory mechanism in the postprandial glucose response, with a particular focus on the mechanism of intestinal glucose absorption. Indeed, despite of many experimental observations, this question remains poorly investigated. Both whole-body physiological and cellular level will be considered. We will adopt a systems biology approach based on formal computational models enhanced by wet-lab experiments. Unlike all the models already available and defined by means of differential equations, we will propose to work with reaction networks. Those are metamodels that add a graph structure to ordinary differential equations (ODEs) and allow for a wider range of analysis methods from computational systems biology. We will also study novel analysis methods for reaction networks able to deal with aspects of postprandial glucose response and diabetes. The hope is to improve the identification of the causes of T2D and, in the longer run, the prediction of appropriate therapies based on reaction networks.

Adipocyte stem cells (ASC) are key regulators of adipose tissue growth in obesity and the consortium recently uncovered a crucial role of adipose tissue resident macrophages in regulating ASC fate and functions. The first aim of our research proposal is to prove and decode using unique in vivo models the interplay between a specific subset of adipose tissue macrophage and ASC. These preclinical observations will be confirmed in human fat by exploring in depth the metabolic cross-talk between adipose tissue resident macrophages and ASC at the spatial and single-cell levels using cutting-edge technologies in lean and obese patients. This will enable the generation of a comprehensive multi-dimensional omics cell atlas of human adipose tissue in health and disease. Strong of their complementary expertise, our consortium will also build human adipose tissue organoid derived from obese patient induced pluripotent stem cells (iPSC) containing macrophages to further model and decipher metabolic and adipogenic processes. In addition, new metabolic tracing capabilities will be developed to identify at the molecular level the origin and fate of metabolites and their contribution in adipose tissue growth (adipogenesis). Such macrophage-sufficient adipose tissue organoid platform will allow to validate mechanisms inferred from our multi-omics cell atlas and to test potential interventions.

Acute effect of metformin on intestinal sodium-glucose co-transport Metformin is widely used to treat type 2 diabetes but its mechanisms of action remain uncertain. Converging evidences now indicate that this non metabolized agent might primarily act in the gut. Preliminary data obtained by the partners suggest that metformin reduces intestinal glucose absorption by modulating active sodium-glucose cotransport. The overall objective of this project is to demonstrate this unexpected acute effect of metformin on intestinal sodium-glucose co-transport in preclinical models and its clinical relevance for the treatment of type 2 diabetes. The specific aims are (1) to explore the acute effect of metformin on active sodium-glucose co-transport in cellular models and genetically modified mice; (2) to characterize the acute effect of metformin on intestinal glucose absorption and postprandial metabolic signature in a large animal model, and (3) to assess its clinical relevance on intestinal glucose transport in patients with type 2 diabetes. The uncovering of a novel mechanism of action of metformin will contribute to the axes 4 and 7 of challenge B4. By promoting a more effective use of this widely used antidiabetic drug, this project will potentially impact millions of patients worldwide.

Fatty liver diseases among which alcoholic and non-alcoholic steatohepatitis [(N)ASH] have become a major health issue worldwide as they represent a major cause of liver failure and cancer. This is due to liver insult leading to fibrosis, a detrimental excess of extracellular matrix (ECM) deposition. The main contributors to this process are hepatic stellate cells (HSCs) which undergo myofibroblastic activation during (N)ASH development acquiring an uncontrolled ECM protein production phenotype. Despite being of central clinical importance regarding (N)ASH, how HSC activation is orchestrated at the molecular level has remained poorly defined. Bioinformatics analyses have allowed us to identify an unforeseen transcription factor, which drives HSC profibrotic activation. By combining functional genomics, in-vivo mouse models as well as the study of human liver biopsies, our project will allow to define clinically relevant novel molecular mechanisms involved in HSC-driven liver fibrosis.