Department of Anatomy and Convergence Medical Science, Bio Antiaging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam 52727, Korea.
Int J Mol Sci. 2020 Sep 30;21(19):7225. doi: 10.3390/ijms21197225.
Obesity-induced adipocyte apoptosis promotes inflammation and insulin resistance. Src homology domain-containing inositol 5'-phosphatase 1 (SHIP1) is a key factor of apoptosis and inflammation. However, the role of SHIP1 in obesity-induced adipocyte apoptosis and autophagy is unclear. We found that diet-induced obesity (DIO) mice have significantly greater crown-like structures and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive cells than ob/ob or control mice. Using RNA sequencing (RNA-seq) analysis, we identified that the apoptosis- and inflammation-related gene Ship1 is upregulated in DIO and ob/ob mice compared with control mice. In particular, DIO mice had more SHIP1-positive macrophages and lysosomal-associated membrane protein 1 (LAMP1) as well as a higher B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio compared with ob/ob or control mice. Furthermore, caloric restriction attenuated adipose tissue inflammation, apoptosis, and autophagy by reversing increases in SHIP1-associated macrophages, Bax/Bcl2-ratio, and autophagy in DIO and ob/ob mice. These results demonstrate that DIO, not ob/ob, aggravates adipocyte inflammation, apoptosis, and autophagy due to differential SHIP1 expression. The evidence of decreased SHIP1-mediated inflammation, apoptosis, and autophagy indicates new therapeutic approaches for obesity-induced chronic inflammatory diseases.
肥胖诱导的脂肪细胞凋亡促进炎症和胰岛素抵抗。Src 同源结构域内含肌醇 5'-磷酸酶 1（SHIP1）是凋亡和炎症的关键因素。然而，SHIP1 在肥胖诱导的脂肪细胞凋亡和自噬中的作用尚不清楚。我们发现，饮食诱导的肥胖（DIO）小鼠的冠状结构和末端脱氧核苷酸转移酶脱氧尿苷三磷酸（dUTP）末端标记（TUNEL）阳性细胞明显多于 ob/ob 或对照小鼠。通过 RNA 测序（RNA-seq）分析，我们发现与对照小鼠相比，凋亡和炎症相关基因 Ship1 在 DIO 和 ob/ob 小鼠中上调。特别是，与 ob/ob 或对照小鼠相比，DIO 小鼠具有更多的 SHIP1 阳性巨噬细胞和溶酶体相关膜蛋白 1（LAMP1）以及更高的 B 细胞淋巴瘤 2（Bcl-2）相关 X 蛋白（Bax）/Bcl-2 比值。此外，热量限制通过逆转 DIO 和 ob/ob 小鼠中与 SHIP1 相关的巨噬细胞、Bax/Bcl2 比值和自噬的增加，减轻了脂肪组织炎症、凋亡和自噬。这些结果表明，DIO 而非 ob/ob 由于 SHIP1 表达的差异加剧了脂肪细胞炎症、凋亡和自噬。SHIP1 介导的炎症、凋亡和自噬减少的证据表明，肥胖诱导的慢性炎症性疾病有新的治疗方法。
