BRITE SIGNED

Project "BRITE" data sheet

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 Project objective

Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.