抑制脂肪组织的脂生成可重新编程产热和 PPARγ 的激活，从而减少饮食诱导的肥胖。
Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity.
机构信息
Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
出版信息
Cell Metab. 2012 Aug 8;16(2):189-201. doi: 10.1016/j.cmet.2012.06.013.
De novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPARγ) modulates endogenous PPARγ activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPARγ transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPARγ and treatment of 3T3-L1 cells with one such ether lipid increased PPARγ transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPARγ transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPARγ-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
脂肪细胞中的从头脂肪生成（de novo lipogenesis），尤其是在高脂肪喂养的情况下，其机制尚未完全清楚。我们证明了一个包含脂肪酸合酶（fatty acid synthase，FAS）和 PexRAP（过氧化物酶体还原酶激活 PPARγ）的脂肪细胞脂肪生成途径，调节内源性 PPARγ 的激活和肥胖。成年脂肪组织中缺乏 FAS 的小鼠表现出能量消耗增加、皮下脂肪组织中棕色脂肪样脂肪细胞增加以及对饮食诱导肥胖的抵抗力增强。胚胎成纤维细胞中 FAS 的敲低降低了 PPARγ 的转录活性和脂肪生成。依赖 FAS 的烷基醚磷脂种类与 PPARγ 相关，并且用其中一种醚脂质处理 3T3-L1 细胞可增加 PPARγ 的转录活性。PexRAP 是烷基醚脂质合成所必需的一种蛋白质，与过氧化物酶体相关，并在脂肪生成过程中诱导表达。细胞中 PexRAP 的敲低降低了 PPARγ 的转录活性和脂肪生成。小鼠中 PexRAP 的敲低降低了 PPARγ 依赖性基因的表达，并减少了饮食诱导的肥胖。这些发现表明，抑制 PexRAP 或相关的脂肪生成酶可能可用于治疗肥胖症和糖尿病。
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