Obesity is associated with low-grade chronic inflammation, which mechanism and treatment are limited. Focusing on the M2 polarization of adipose tissue macrophages (ATMs) will provide a novel target for the treatment of obesity-related chronic inflammatory diseases. In our previous research, we found Zinc-alpha2-glycoprotein (ZAG) treatment displayed reduced pro-inflammatory cytokines and enhanced M2 markers expression levels in LPS-induced macrophages. However, whether ZAG could regulate M2 proportion in ATMs via β3-adrenergic receptors remains unclear. Hence, we hypothesized that ZAG modulates M2 polarization of ATMs are stimulated by β3-adrenergic receptors mediated activation of downstream effectors PAK-STAT3 and p38MAPK-STAT6 signaling pathway. This study will systematically investigate the functions and mechanisms of ZAG in improving obesity-related IR and regulating M2 proportion in ATMs from establishing the adipose tissue specific ZAG knockout and transgenic model. Thus, our research will highlight a novel pathway for ZAG regulating obesity-related chronic inflammatory, and provide a new therapeutic target for obesity.
肥胖是一种慢性和低度炎症性疾病,发生机制尚未明确,预防和治疗手段更是有限。调节脂肪组织巨噬细胞(ATMs)向抗炎M2型极化可能是改善肥胖脂肪组织慢性炎症的重要手段。本项目组前期研究发现锌α2糖蛋白(ZAG)是一种抗炎细胞因子,抑制巨噬细胞产生炎症因子,并且上调M2型ATMs标志基因表达。ZAG是否可通过结合ATMs的β3肾上腺素受体(β3-AR)而促进M2极化不清楚。由此我们提出科学假说:ZAG可通过激活β3-AR,启动PAK-STAT3及p38MAPK-STAT6途径,调节ATMs向M2型极化改善脂肪组织炎症。该项目将结合体内外实验,通过脂肪组织特异性ZAG敲除和转基因小鼠模型,明确ZAG在改善脂肪组织炎症中的作用,探讨ZAG通过β3-AR激活M2关键转录因子STAT3及STAT6的信号通路,阐明ZAG抑制脂肪组织炎症抗肥胖的新机制,为临床治疗肥胖提供一个新的途径。
肥胖是一种慢性和低度炎症性疾病,发生机制尚未明确,预防和治疗手段更是有限。调节脂肪组织巨噬细胞(ATMs)向抗炎M2型极化可能是改善肥胖脂肪组织慢性炎症的重要手段。本项目组前期研究发现锌α2糖蛋白(ZAG)是一种抗炎细胞因子,可抑制高脂诱导的脂肪肝炎,但ZAG是否也可抑制脂肪组织慢性炎症目前尚不清楚。通过本项目的研究我们首次发现在肥胖人群中,网膜内脏脂肪ZAG表达显著降低,与HOMA-IR及促炎因子呈负相关而与抗炎因子呈正相关。此外,我们首次发现脂肪组织特异性过表达ZAG能够减轻高脂饮食诱导的肥胖小鼠的体重,改善胰岛素抵抗,并且能够显著促进小鼠附睾内脏脂肪组织巨噬细胞向M2极化进而改善脂肪组织慢性炎症。机制上,我们阐明了ZAG抑制脂肪组织炎症抗肥胖的新机制:ZAG是通过结合巨噬细胞β3-AR,进而激活PKA-STAT3信号途径促进巨噬细胞向M2极化。本研究将为临床治疗肥胖提供一个新的途径。
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数据更新时间:2023-05-31
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