CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization.
CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization.
复制标题
CLSTN3β强制脂肪细胞多生对象，以促进脂质利用。
DOI：
10.1038/s41586-022-05507-1
复制
发表时间：
2023-01
期刊：
影响因子：
64.8
通讯作者：
Tontonoz, Peter
中科院分区：
文献类型：
--
作者：
Qian, Kevin;Tol, Marcus J.;Wu, Jin;Uchiyama, Lauren F.;Xiao, Xu;Cui, Liujuan;Bedard, Alexander H.;Weston, Thomas A.;Rajendran, Pradeep S.;Vergnes, Laurent;Shimanaka, Yuta;Yin, Yesheng;Jami-Alahmadi, Yasaman;Cohn, Whitaker;Bajar, Bryce T.;Lin, Chia-Ho;Jin, Benita;DeNardo, Laura A.;Black, Douglas L.;Whitelegge, Julian P.;Wohlschlegel, James A.;Reue, Karen;Shivkumar, Kalyanam;Chen, Feng-Jung;Young, Stephen G.;Li, Peng;Tontonoz, Peter
多房脂肪细胞是产热脂肪组织的标志，但促使这种细胞表型的因素在很大程度上是未知的。在这里，我们表明，仅存在于胎盘哺乳动物中的Clstn 3基因座（CLSTN 3 β）的脂肪细胞选择性产物通过限制脂滴（LD）扩增促进了储存甘油三酯的有效利用。CLSTN 3 β是一种整合的内质网（ER）膜蛋白，通过保守的发夹样结构域定位于ER-LD接触位点。缺乏CLSTN 3 β的小鼠具有异常的LD形态和棕色脂肪组织中改变的底物使用，并且尽管肾上腺素能信号传导没有缺陷，但对冷诱导的体温过低更敏感。相反，CLSTN 3 β的强制表达足以在培养的细胞和脂肪组织中实施多室LD表型。CLSTN 3 β与诱导细胞死亡的DFFA样效应蛋白相关，并削弱其在LD之间转移脂质的能力，从而限制LD融合和扩增。在功能上，CLSTN 3 β表达脂肪细胞中增加的LD表面积促进脂解机制的参与并促进脂肪酸氧化。在人类脂肪中，CLSTN 3B是多室脂肪细胞的选择性标志物。这些发现定义了一个分子机制，调节LD的形式和功能，以促进产热脂肪细胞的脂质利用。
Multilocular adipocytes are a hallmark of thermogenic adipose tissue, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3β) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3β is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER–LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3β have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3β is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3β associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3β-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.
登录
查看更多内容
影响因子：
14.8
作者：
Hung V;Udeshi ND;Lam SS;Loh KH;Cox KJ;Pedram K;Carr SA;Ting AY
通讯作者：
Ting AY
影响因子：
14.9
作者：
Buchan, Daniel W. A.;Jones, David T.
通讯作者：
Jones, David T.
影响因子：
64.8
作者：
Guo, Yi;Walther, Tobias C.;Farese, Robert V., Jr.
通讯作者：
Farese, Robert V., Jr.
影响因子：
20.8
作者：
de Jong, Jasper M. A.;Sun, Wenfei;Petrovic, Natasa
通讯作者：
Petrovic, Natasa
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B