Ghrelin receptor regulates adipose tissue inflammation in aging.
Ghrelin receptor regulates adipose tissue inflammation in aging.
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DOI：
10.18632/aging.100888
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
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作者：
Lin L;Lee JH;Buras ED;Yu K;Wang R;Smith CW;Wu H;Sheikh-Hamad D;Sun Y
衰老通常与低度脂肪炎症有关，而低度脂肪炎症又与胰岛素抵抗密切相关。生长素释放肽是唯一一种循环的促食欲激素，已知会增加肥胖和胰岛素抵抗。我们之前报道过，生长激素释放肽受体、生长激素促分泌素受体（GHS-R）的表达在衰老过程中脂肪组织中增加，并且老年 Ghsr−/− 小鼠表现出瘦弱和胰岛素敏感的表型。巨噬细胞是脂肪组织炎症的主要介质，由促炎 M1 和抗炎 M2 亚型组成。在这里，我们发现在老年小鼠中，GHS-R 消融促进巨噬细胞表型向抗炎 M2 转变。年老的 Ghsr−/− 小鼠的白色和棕色脂肪组织中的巨噬细胞浸润、M1/M2 比率和促炎细胞因子表达减少。我们还发现，老年 Ghsr−/− 小鼠的腹腔巨噬细胞产生更高的去甲肾上腺素，这与替代激活的 M2 巨噬细胞的增加一致。我们的数据进一步表明，GHS-R 在巨噬细胞中具有细胞自主作用，GHS-R 拮抗剂可抑制脂多糖 (LPS) 诱导的巨噬细胞炎症反应。总的来说，我们的研究表明，生长素释放肽信号在衰老过程中的巨噬细胞极化和脂肪组织炎症中具有重要作用。 GHS-R 拮抗剂可能作为年龄相关脂肪组织炎症和胰岛素抵抗的新型有效治疗选择。
Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.