Membrane Metallo-Endopeptidase (Neprilysin) Regulates Inflammatory Response and Insulin Signaling in White Preadipocytes (Microarray Expression). Membrane Metallo-Endopeptidase (Neprilysin) Regulates Inflammatory Response and Insulin Signaling in White Preadipocytes (Microarray Expression)

Accumulation of subcutaneous white adipose tissue (WAT) is associated with increased insulin sensitivity, low levels of inflammation and a generally metabolically-healthy state, whereas accumulation of visceral adipose tissue is associated with insulin resistance, adipose tissue inflammation and metabolic syndrome. Membrane Metallo-Endopeptidase (MME/Neprislyin) is an extracellular, membrane-bound protease enriched in subcutaneous WAT that can target degradation of a variety of peptides, including insulin, IL6, and β-amyloids. Here, we show that MME in white preadipocytes is differently expressed in subcutaneous vs visceral WAT, and favors insulin signaling and a low inflammatory response. Thus, knockdown of MME in preadipocytes increases the inflammatory response to substance P and amyloidβ aggregates. This is associated with increased basal insulin signaling and decreased insulin-stimulated signaling. Moreover, MME differentially regulates the internalization and turnover of the α/β subunits of the insulin receptor. Thus, MME is a novel regulator of the insulin receptor in adipose tissue and may serve as a therapeutic target to increase insulin sensitivity and decrease inflammatory susceptibility. Overall design: FACS Isolated preaadipocytes from subcutaneous and perigonadal (intraabdominal) adipose tissue of mice were used for RNA extraction and hybridization on Affymetrix microarrays.

皮下白色脂肪组织（subcutaneous white adipose tissue, WAT）的堆积与胰岛素敏感性升高、炎症水平低下及整体代谢健康状态密切相关，而内脏脂肪组织的堆积则与胰岛素抵抗、脂肪组织炎症及代谢综合征的发生发展紧密关联。膜金属内肽酶（Membrane Metallo-Endopeptidase, MME/Neprilysin）是一类富集于皮下WAT的细胞外膜结合型蛋白酶，可靶向降解包括胰岛素、白细胞介素6（IL6）以及β-淀粉样蛋白在内的多种肽类物质。本研究证实，白色脂肪前体细胞中的MME在皮下与内脏WAT中的表达存在显著差异，且其可促进胰岛素信号通路活化并维持低炎症应答状态。因此，在脂肪前体细胞中敲低MME的表达，会增强机体对P物质与β-淀粉样蛋白聚集体的炎症应答。该现象与基础胰岛素信号通路活性升高及胰岛素刺激的信号通路活性降低密切相关。此外，MME可差异性调控胰岛素受体α/β亚基的内吞与周转过程。综上，MME是脂肪组织中胰岛素受体的新型调控因子，有望成为提升胰岛素敏感性、降低炎症易感性的治疗靶点。实验整体设计：从小鼠皮下及附睾旁（腹腔内）脂肪组织中通过荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）分离得到的脂肪前体细胞，被用于RNA提取及Affymetrix基因芯片杂交实验。