Transcriptional control of brown preadipocyte commitment by PITX2

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In mammals, brown adipose tissue (BAT) serves as a key heat-producing organ required to maintain body temperature and homeothermy. In response to cold, activation of the sympathetic nervous system rapidly turns on lipolysis and thermogenesis along with a specific transcriptional program required for heat production in brown adipocytes. Over the last years, it was shown that BAT is very dynamic. In response to chronic adrenergic stimulation (cold exposure or treatments with B3-adrenergic receptor agonists), BAT expands its mass through a combination of hyperplasia and hypertrophy and increases mitochondrial number to support thermogenesis. While there has been significant advances in the understanding of the molecular mechanisms regulating terminal differentiation and mitochondrial biogenesis in brown adipocytes, the identity of BAT progenitors and the events that regulate their adipogenic conversion are only emerging.******In order to identify new factors playing early roles in brown adipocyte commitment and development, we have performed a series of experiments based on an approach that we previously published in Cell Reports (Secco et al. 2017). These experiments led to the identification of Paired-like homeodomain transcription factor 2 (PITX2) as a new factor that could play crucial roles in promoting brown fat cell development. PITX2 is a transcription factor that acts during early embryonic development to control the formation of many parts of the body. Three major isoforms of PITX2 (PITX2A, PITX2B and PITX2C) are produced by alternative splicing. Whether PITX2 isoforms play roles in regulating brown preadipocyte commitment and BAT development has never been described in the literature. ******Building upon my previous work and expertise on adipose tissue, adipogenesis and cell biology, this program aims to characterize the mechanisms by which PITX2 controls brown adipocyte commitment and differentiation. The objectives of this proposal for the next 5 years are to: ******1) Define the role of PITX2 isoforms in regulating brown adipogenic commitment and thermogenic gene expression.***2) Define how PITX2 isoforms control the adipogenic potential of brown preadipocytes.***3) Study the identity of PITX2 expressing cells and characterize their response to conditions promoting BAT hyperplasia.******Studying the molecular mechanisms controlling brown adipocyte development will provide crucial information to understand how these cells are recruited to allow animals to adapt to cold. Beyond its direct impact on BAT biology, this project has the potential to reveal new regulatory pathways to improve the general understanding of the processes controlling cell differentiation and tissue development. *****