Transcriptional control of brown preadipocyte commitment by PITX2

在哺乳动物中，棕色脂肪组织（BAT）是维持体温和恒温所需的关键产热器官。作为对寒冷的反应，交感神经系统的激活迅速开启了脂肪分解和产热，并伴随着棕色脂肪细胞产热所需的特定转录程序。过去几年的情况表明，BAT是非常有活力的。在慢性肾上腺素能刺激（冷暴露或b3肾上腺素能受体激动剂治疗）的反应中，BAT通过增生和肥大的结合扩大其质量，并增加线粒体数量以支持产热。虽然在棕色脂肪细胞中调节终末分化和线粒体生物发生的分子机制的理解方面取得了重大进展，但BAT祖细胞的身份和调节其成脂转化的事件才刚刚出现。******为了确定在棕色脂肪细胞承诺和发育中起早期作用的新因素，我们基于之前发表在Cell Reports （Secco et al. 2017）上的方法进行了一系列实验。这些实验鉴定出配对样同源结构域转录因子2（成对样同源结构域转录因子2，PITX2）是一个可能在促进棕色脂肪细胞发育中起关键作用的新因子。PITX2是一种转录因子，在胚胎早期发育过程中起作用，控制身体许多部位的形成。PITX2的三个主要亚型（PITX2A， PITX2B和PITX2C）是通过选择性剪接产生的。PITX2亚型是否在调节褐色前脂肪细胞承诺和BAT发育中发挥作用尚未见文献报道。******基于我之前在脂肪组织、脂肪形成和细胞生物学方面的工作和专业知识，这个项目旨在描述PITX2控制棕色脂肪细胞承诺和分化的机制。在接下来的5年里，我们的目标是：******1)确定PITX2亚型在调节棕色脂肪生成和产热基因表达中的作用。***2)确定PITX2亚型如何控制棕色前脂肪细胞的成脂潜能。***3)研究PITX2表达细胞的特性及其对促进BAT增生条件的反应。******研究控制棕色脂肪细胞发育的分子机制将为了解这些细胞如何被招募以使动物适应寒冷提供关键信息。除了对BAT生物学的直接影响外，该项目还有可能揭示新的调控途径，以提高对控制细胞分化和组织发育过程的一般理解。＊＊＊＊＊

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. *****