Laboratory of Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, and the Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
Diabetes. 2012 Nov;61(11):2814-22. doi: 10.2337/db12-0176. Epub 2012 Aug 13.
Adipocyte renewal from preadipocytes has been shown to occur throughout life and to contribute to obesity, yet very little is known about the molecular circuits that control preadipocyte expansion. The soluble form of the preadipocyte factor (also known as pref-1) delta-like 1 homolog (DLK1(S)) is known to inhibit adipogenic differentiation; however, the impact of DLK1 isoforms on preadipocyte proliferation remains to be determined. We generated preadipocytes with different levels of DLK1 and examined differentially affected gene pathways, which were functionally tested in vitro and confirmed in vivo. Here, we demonstrate for the first time that only membrane-bound DLK1 (DLK1(M)) exhibits a substantial repression effect on preadipocyte proliferation. Thus, by independently manipulating DLK1 isoform levels, we established that DLK1(M) inhibits G1-to-S-phase cell cycle progression and thereby strongly inhibits preadipocyte proliferation in vitro. Adult DLK1-null mice exhibit higher fat amounts than wild-type controls, and our in vivo analysis demonstrates that this may be explained by a marked increase in preadipocyte replication. Together, these data imply a major dual inhibitory function of DLK1 on adipogenesis, which places DLK1 as a master regulator of preadipocyte homeostasis, suggesting that DLK1 manipulation may open new avenues in obesity treatment.
脂肪细胞可以从前脂肪细胞中更新，这种现象在整个生命周期中都存在，并导致肥胖，但人们对控制前脂肪细胞扩增的分子回路知之甚少。已知前脂肪细胞因子（也称为 pref-1）delta 样 1 同源物（DLK1(S)）的可溶性形式可抑制脂肪生成分化；然而，DLK1 同工型对前脂肪细胞增殖的影响仍有待确定。我们生成了具有不同 DLK1 水平的前脂肪细胞，并检查了受不同影响的基因途径，这些途径在体外进行了功能测试，并在体内得到了证实。在这里，我们首次证明只有膜结合的 DLK1（DLK1(M)）对前脂肪细胞增殖表现出显著的抑制作用。因此，通过独立操纵 DLK1 同工型水平，我们确定 DLK1(M)抑制 G1 期到 S 期细胞周期进程，从而强烈抑制体外前脂肪细胞增殖。成年的 DLK1 敲除小鼠比野生型对照具有更多的脂肪量，我们的体内分析表明，这可能是由于前脂肪细胞复制的显著增加所导致的。总之，这些数据表明 DLK1 对脂肪生成具有主要的双重抑制功能，将 DLK1 置于前脂肪细胞动态平衡的主调控因子的位置，这表明 DLK1 的操纵可能为肥胖症的治疗开辟新途径。
