PLoS One：胖子的减肥之苦

胖人总是抱怨，喝口凉水都能长肉。为什么越胖的人越容易长肉呢？日本一个研究小组最新研究发现了其中的部分机制。

东京大学佐藤隆一郎领导的研究小组在新一期《PLoS ONE》上报告说，他们发现脂肪细胞内的脂滴可以增强负责制造脂肪的基因功能，从而制造出更多脂滴，由此形成恶性循环。因此，脂肪多的人就更容易制造新的脂肪。

脂滴占据脂肪细胞的大部分空间，是中性脂质的主要贮存场所。研究人员之前就已经知道脂肪细胞能够持续制造大量脂滴，导致脂肪堆积，从而形成肥胖，但是一直不清楚其详细机制。

研究小组通过基因干预手段，使得实验鼠体内无法形成脂滴，结果发现制造脂肪的 SREBP1 基因功能也比一般实验鼠减弱许多。反之，当恢复脂滴制造时， SREBP1 的功能得到加强，脂肪蓄积量也随之增加。

研究人员认为，脂滴促进制造脂肪，脂肪形成后反过来又增加了脂滴，这种循环就是肥胖机制。如果能够开发出阻止这种循环的药物，就有可能预防肥胖。

Perilipin-Mediated Lipid Droplet Formation in Adipocytes Promotes Sterol Regulatory Element-Binding Protein-1 Processing and Triacylglyceride Accumulation
Abstract
Sterol regulatory element-binding protein-1 (SREBP-1) has been thought to be a critical factor that assists adipogenesis. During adipogenesis SREBP-1 stimulates lipogenic gene expression, and peroxisome proliferator-activated receptor γ (PPARγ) enhances perilipin (plin) gene expression, resulting in generating lipid droplets (LDs) to store triacylglycerol (TAG) in adipocytes. Plin coats adipocyte LDs and protects them from lipolysis. Here we show in white adipose tissue (WAT) of plin−/− mice that nuclear active SREBP-1 and its target gene expression, but not nuclear SREBP-2, significantly decreased on attenuated LD formation. When plin−/− mouse embryonic fibroblasts (MEFs) differentiated into adipocytes, attenuated LDs were formed and nuclear SREBP-1 decreased, but enforced plin expression restored them to their original state. Since LDs are largely derived from the endoplasmic reticulum (ER), alterations in the ER cholesterol content were investigated during adipogenesis of 3T3-L1 cells. The ER cholesterol greatly reduced in differentiated adipocytes. The ER cholesterol level in plin−/− WAT was significantly higher than that of wild-type mice, suggesting that increased LD formation caused a change in ER environment along with a decrease in cholesterol. When GFP-SREBP-1 fusion proteins were exogenously expressed in 3T3-L1 cells, a mutant protein lacking the S1P cleavage site was poorly processed during adipogenesis, providing evidence of the increased canonical pathway for SREBP processing in which SREBP-1 is activated by two cleavage enzymes in the Golgi. Therefore, LD biogenesis may create the ER microenvironment favorable for SREBP-1 activation. We describe the novel interplay between LD formation and SREBP-1 activation through a positive feedback loop.