Regulation of Activin Receptor-like kinase 7 (ALK7) by cGMP in adipocytes

在过去的几十年里，肥胖成为全球范围内一个主要的健康问题，影响着超过10亿人。到目前为止，参与脂肪质量调节的过程和分子在很大程度上仍然没有解决。棕色脂肪组织(BAT)是对抗肥胖的一个有趣的潜在靶子，因为它能够以热的形式传播能量(非颤抖生热)。重要的是，2009年，几个研究小组发表了一篇文章，指出代谢活跃的蝙蝠也存在于成人体内。自从这一新发现以来，BAT引起了人们的极大兴趣，进一步加强了这一发现，即分散的棕色样脂肪细胞(所谓的米色或布利特细胞)存在于白色脂肪组织(WAT)中。在这个项目中，我们将重点研究激活素受体样激酶7(ALK7)，它是转化生长因子-β受体家族的成员。我们和其他人证明了cGMP信号对棕色和白色脂肪细胞的发育都是必不可少的。在对cGMP信号通路下游成分的筛选中，我们发现cGMP高度调节棕色脂肪细胞中ALK7的表达。到目前为止，ALK7在棕色脂肪细胞中的功能尚不清楚，我们的初步数据表明，ALK7在蝙蝠分化过程中发挥了作用。因此，我们将分析ALK7在BAT和WAT中的功能，以及在白色脂肪细胞褐化过程中的作用。鉴于cGMP信号在脂肪形成中的重要作用，我们将在体外和体内研究cGMP信号通路和ALK7/转化生长因子-β/激活素信号在棕色、米色和白色脂肪细胞中的相互作用。综上所述，我们的目的不仅是为了确定ALK7在脂肪细胞中的功能，而且也是为了了解ALK7/转化生长因子-β信号与cGMP信号之间的生理相关性。

In last decades, obesity became a major health issue worldwide affecting more than one billion subjects. Processes as well as molecules involved in fat mass regulation remain largely unresolved up to now. Brown adipose tissue (BAT) is an interesting potential target to fight obesity, because it is capable of disseminating energy as heat (nonshivering thermogenesis). Importantly, in 2009 several groups published that metabolically active BAT is also present in human adults. Since this rediscovery, BAT has gained much interest, which is further intensified by the finding that dissipated brown-like adipocytes (so called beige or brite cells) occur within white adipose tissue (WAT). In this project, we will focus on the activin receptor-like kinase 7 (ALK7), a member of the TGF-beta receptor family. We and others demonstrated that cGMP signaling is essential for the development of both brown and white adipocytes. During a screen for downstream components of the cGMP signaling pathway, we found that cGMP highly regulates expression of ALK7 in brown adipocytes. So far nothing is known about the function of ALK7 in brown adipocytes, our preliminary data indicate that ALK7 plays a role in BAT differentiation. Therefore, we will analyze the function of ALK7 in BAT and WAT, as well as during browning of white adipocytes. Given the crucial role of cGMP signaling in adipogenesis, we will investigate the interaction between the cGMP signaling cascade and ALK7/ TGF-beta /Activin signaling in brown, beige and white adipocytes in vitro and in vivo. Taken together, our aim is to identify not only the function of ALK7 in adipocytes, but also to understand the physiological relevance of the crosstalk between ALK7/ TGF-beta and cGMP signaling.