德国波恩大学Alexander Pfeifer团队发现，EPAC1可促进棕色脂肪的生长和米色脂肪的生成。2024年1月9日，《自然—细胞生物学》杂志在线发表了这项成果。

研究人员发现cAMP结合蛋白EPAC1是适应性棕色脂肪组织（BAT）生长的核心调节因子。在体内，选择性药理激活EPAC1可增加BAT质量和白色脂肪的棕色化，从而增加能量消耗并减少饮食引起的肥胖。从机理上讲，EPAC1协调了一个增殖调节因子网络，该网络专门作用于产热脂肪细胞，而不是白色脂肪细胞。研究人员将EPAC1的作用定位在PDGFRα阳性的脂肪细胞前体上，这些细胞中EPAC1的缺失会阻碍BAT的生长并加重饮食诱导的肥胖。

重要的是，EPAC1的激活能增强人类棕色脂肪细胞和人类棕色脂肪类器官的增殖和分化。值得注意的是，RAPGEF3（编码EPAC1）的编码变体与体重指数呈正相关，它能抑制去甲肾上腺素诱导的棕色脂肪细胞增殖。因此，EPAC1可能是一个有吸引力的靶点，可用于提高产热脂肪细胞的数量和能量消耗，从而防治代谢性疾病。

据了解，BAT是一个核心的产热器官，能增强能量消耗和心脏代谢健康。然而，专门增加产热脂肪细胞数量的调节剂仍是一个尚未满足的需求。

附：英文原文

Title: EPAC1 enhances brown fat growth and beige adipogenesis

Author: Reverte-Salisa, Laia, Siddig, Sana, Hildebrand, Staffan, Yao, Xi, Zurkovic, Jelena, Jaeckstein, Michelle Y., Heeren, Joerg, Lezoualch, Frank, Krahmer, Natalie, Pfeifer, Alexander

Issue&Volume: 2024-01-09

Abstract: Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.

DOI: 10.1038/s41556-023-01311-9

Source: https://www.nature.com/articles/s41556-023-01311-9