Defining an atypical GPCR as a novel regulator of transcriptional reprogramming of metabolism – GPCR-Metab

Obesity/overweight and type 2 diabetes (T2D) represent serious health problems as they increase the incidence of cardiovascular disease and cancer and are a major cause of premature mortality. Among the multifactorial origins of these diseases, it is well documented that altered adipose tissue and hypothalamus function leads to major organ dysfunction and lies at the heart of the obesity and T2D pandemic. Beige fat cells, scattered in white adipose tissue, produce mitochondrial proteins involved in the conversion of energy into heat. Specific activation of these cells in white adipose tissue would allow its "browning", the removal of excess fat and glucose, making it an excellent treatment for obesity and T2D. On the contrary, its alteration contributes to metabolic disorders. It is also known that impaired communication between the brain and the periphery is another causal factor in obesity and T2D. Indeed, in a specific site of the hypothalamus, at the interface with the bloodstream, blood-brain communication is ensured by specialised cells of the median eminence, the tanycytes. Tanycytes are involved in various processes controlling energy homeostasis, and their dysfunction leads to the development of obesity and T2D. In this context, the GPCR-Metab consortium has discovered that a G protein-coupled receptor (GPCR), whose function is poorly understood, has a novel mechanism of action capable of directly regulating gene transcription and reprogramming metabolic cells, such as adipocytes and tanycytes. Thus, the GPCR-Metab project aims to explore the peripheral function of this receptor in adipocytes and its central action in tanycytes in the physiological regulation of metabolism in order to fully explore its therapeutic potential in obesity and T2D, and to identify new mechanisms of action.