REMADE

The global rise in type 2 diabetes (T2D) and obesity represents a major public health challenge, primarily due to insulin resistance (IR), particularly in the liver. Recent studies have highlighted the central role of mitochondria-associated membranes (MAMs) in the early stages of IR. In particular, I contributed to demonstrating that the nuclear receptor ERRalpha regulates the expression of genes encoding key MAM-related proteins. However, the molecular mechanisms by which overnutrition disrupts MAMs remain poorly understood. Based on these findings, I hypothesize that early transcriptional changes induced by overnutrition lead to MAM dysfunction, thereby promoting the onset of IR and the progression of T2D. This project aims to decipher these early and still underexplored mechanisms to identify new therapeutic targets. It is structured around three main objectives: 1) Identify early MAM alterations induced by overnutrition Using an integrated multi-omics approach, we will analyze ERRalpha liver knockout and wild-type mouse models to uncover molecular signatures associated with the initial phases of hepatic IR. 2) Characterize regulatory pathways involved in MAM function We will investigate how key transcriptional and post-translational regulators control MAM function and their role in the development of IR. 3) Validate findings in human samples Thanks to clinical cohorts, we will assess the translational relevance of the identified mechanisms in human liver tissue. This ANR JCJC will provide new insights into the transcriptional regulation of MAMs and pave the way for novel therapeutic strategies targeting the early stages of T2D.