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

在过去的几十年中，肥胖成为全球范围内影响超过10亿受试者的主要健康问题。到目前为止，参与脂肪量调节的过程和分子在很大程度上仍然没有得到解决。棕色脂肪组织（BAT）是对抗肥胖的一个有趣的潜在目标，因为它能够以热量的形式传播能量（非颤抖性产热）。重要的是，2009年，几个研究小组发表了代谢活跃的BAT也存在于人类成年人中。自从这次重新发现以来，BAT引起了人们的极大兴趣，而在白色脂肪组织（WAT）中存在消散的棕色样脂肪细胞（所谓的米色或棕色细胞）的发现进一步加剧了这种兴趣。在这个项目中，我们将专注于激活素受体样激酶7（ALK 7），TGF-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。在筛选cGMP信号通路的下游组分期间，我们发现cGMP高度调节棕色脂肪细胞中ALK 7的表达。到目前为止，对ALK 7在棕色脂肪细胞中的功能一无所知，我们的初步数据表明ALK 7在BAT分化中起作用。因此，我们将分析ALK 7在BAT和WAT中以及在白色脂肪细胞的布朗宁期间的功能。鉴于cGMP信号传导在脂肪形成中的关键作用，我们将在体外和体内研究棕色、米色和白色脂肪细胞中cGMP信号传导级联与ALK 7/TGF-β/激活素信号传导之间的相互作用。综上所述，我们的目标不仅是确定ALK 7在脂肪细胞中的功能，而且要了解ALK 7/TGF-β和cGMP信号之间的串扰的生理相关性。

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.