Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA.
Obesity (Silver Spring). 2014 Jun;22(6):1485-94. doi: 10.1002/oby.20726. Epub 2014 Mar 8.
To investigate the role of TNF-like weak inducer of apoptosis (TWEAK) in pathological adipose tissue (AT) remodeling and complications of obesity.
Wild type (WT) and TWEAK knockout (KO) mice were fed normal diet (ND) or a high fat diet (HFD) for up to 17 weeks. Adipocyte death was induced using an established transgenic mouse model of inducible adipocyte apoptosis (FAT-ATTAC). Metabolic, biochemical, histologic, and flow cytometric analyses were performed.
TWEAK and its receptor, fibroblast growth factor-inducible molecule 14 (Fn14) were upregulated in gonadal (g)AT of WT mice after HFD week 4 and 24 h after induction of adipocyte apoptosis. Phenotypes of KO and WT mouse were indistinguishable through HFD week 8. However, at week 17 obese KO mice had ∼30% larger gAT adipocytes and gAT mass than WT mice, coincident with reduced adipocyte death, enhanced insulin signaling, Th2/M2 immune skewing, fewer thick collagen fibers, and altered expression of extracellular matrix constituents and modulators that is consistent with reduced fibrosis and larger adipocytes. KO mice were less steatotic and became more insulin sensitive and glucose tolerant than WT mice after HFD week 12.
TWEAK constrains "healthy" gAT expansion and promotes metabolic complications in severe obesity.
研究肿瘤坏死因子样凋亡弱诱导剂（TWEAK）在病理性脂肪组织（AT）重塑和肥胖并发症中的作用。
将野生型（WT）和 TWEAK 敲除（KO）小鼠分别用正常饮食（ND）或高脂肪饮食（HFD）喂养长达 17 周。使用已建立的诱导脂肪细胞凋亡的转基因小鼠模型（FAT-ATTAC）诱导脂肪细胞死亡。进行代谢、生化、组织学和流式细胞术分析。
WT 小鼠的性腺（g）AT 在 HFD 第 4 周和脂肪细胞凋亡后 24 小时 TWEAK 和其受体成纤维细胞生长因子诱导分子 14（Fn14）上调。在 HFD 第 8 周前，KO 和 WT 小鼠的表型没有区别。然而，在第 17 周时，肥胖的 KO 小鼠的 gAT 脂肪细胞和 gAT 质量比 WT 小鼠大 30%左右，这与脂肪细胞死亡减少、胰岛素信号增强、Th2/M2 免疫偏向、胶原纤维变厚减少以及细胞外基质成分和调节剂的表达改变有关，这些改变与纤维化减少和脂肪细胞增大一致。与 WT 小鼠相比，KO 小鼠在 HFD 第 12 周后脂肪变性更少，胰岛素敏感性和葡萄糖耐量更高。
TWEAK 限制了“健康”的 gAT 扩张，并促进了严重肥胖的代谢并发症。
