SMRT-GPS2 co-repressor complex: molecular sensor of adipose tissue inflammation in human obesity – CONRAD

Obesity has become a global epidemic and is one the most significant public health challenges of the 21st century. In obesity, chronic low-grade inflammation is thought to alter adipose tissue functions, linking obesity to its numerous co-morbidities, as insulin resistance, type-2 diabetes and cardiovascular diseases. The obese adipose tissue is a site of multiple and overlapping mechanisms that operate at different levels to promote inflammation, including immune cells infiltration and up-regulation of pro-inflammatory signalling pathways and gene expression. These processes are the focus of intense research interest, but remain to be fully deciphered in the adipose tissue. In this context, the overall aim of my project is to investigate the mechanistic control of inflammation at the transcriptional level, specifically in human adipose tissue. I and others recently proposed a new concept related to the control of inflammatory gene transcription, through the NCOR/SMRT co-repressor complexes. I have discovered that the GPS2 subunit of NCOR/SMRT complexes is required for repression of inflammatory genes in hepatocytes and macrophages. This led us to hypothesize that NCOR/SMRT complexes contribute to the regulation of obesity-induced inflammation in adipose tissue. To test this hypothesis, my project aims at deciphering the molecular actions and physiological functions of the NCOR/SMRT co-repressor complexes in adipose tissue. To my knowledge, this novel molecular pathway has never been investigated so far in human or mouse adipose tissue. My major focus will be to i) identify the subset of genes controlled by NCOR, SMRT and GPS2 and their associated epigenetic code in human adipose cells, ii) characterize the metabolic and inflammatory consequences of GPS2 adipose-specific depletion in genetically modified mice and iii) evaluate the relevance of enhancing NCOR/SMRT co-repressor complexes activity to control inflammation in adipose tissue. Overall this project will benefit the Research Community, by improving our basic understanding of the transcriptional control governing obesity-induced inflammation. Since adipose tissue inflammation is recognized as a major pathogenic process in obesity linked metabolic complications, including type 2 diabetes, my research project could lead to define new therapeutic strategies targeting the NCOR/SMRT complexes to ameliorate inflammatory and metabolic status in obese subjects.