BACKGROUND Adipose tissue plays a crucial role in diet- and obesity-related insulin resistance, with implications for several metabolic diseases. Identification of novel target genes and mechanisms that regulate adipocyte function could lead to improved treatment strategies. RND3 (RhoE/Rho8), a Rho-related GTP-binding protein that inhibits Rho kinase (ROCK) signaling, has been linked to diverse diseases such as apoptotic cardiomyopathy, heart failure, cancer and type 2 diabetes, in part by regulating cytoskeleton dynamics and insulin-mediated glucose uptake. RESULTS We here investigated the expression of RND3 in adipose tissue in human obesity, and discovered a role for RND3 in regulating adipocyte metabolism. In cross-sectional and prospective studies, we observed 5-fold increased adipocyte levels of RND3 mRNA in obesity, reduced levels after surgery-induced weight loss, and positive correlations of RND3 mRNA with adipocyte size and surrogate measures of insulin resistance (HOMA2-IR and circulating triglyceride/high-density lipoprotein cholesterol (TAG/HDL-C) ratio). By screening for RND3-dependent gene expression following siRNA-mediated RND3 knockdown in differentiating human adipocytes, we found downregulation of inflammatory genes and upregulation of genes related to adipocyte ipolysis and insulin signaling. Treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), hypoxia or cAMP analogs increased RND3 mRNA levels 1.5-2-fold. Functional assays in primary human adipocytes confirmed that RND3 knockdown reduces cAMP- and isoproterenol-induced lipolysis, which were mimicked by treating cells with ROCK inhibitor. This effect could partly be explained by reduced protein expression of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL). CONCLUSION We here uncovered a novel differential expression of adipose RND3 in obesity and insulin resistance, which may at least partly depend on a causal effect of RND3 on adipocyte lipolysis.

中文翻译：

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Rho GTPase RND3调节脂肪细胞的脂解作用。

背景技术脂肪组织在饮食和肥胖相关的胰岛素抵抗中起着至关重要的作用，涉及几种代谢疾病。鉴定新的靶基因和调节脂肪细胞功能的机制可以导致改善的治疗策略。RND3（RhoE / Rho8）是一种抑制Rho激酶（ROCK）信号的Rho相关GTP结合蛋白，已与多种疾病相关，如凋亡性心肌病，心力衰竭，癌症和2型糖尿病，部分是通过调节细胞骨架动力学来实现的和胰岛素介导的葡萄糖摄取。结果我们在这里研究了RND3在肥胖症患者脂肪组织中的表达，并发现RND3在调节脂肪细胞代谢中的作用。在横断面和前瞻性研究中，我们观察到肥胖人群中RND3 mRNA的脂肪细胞水平增加了5倍，降低手术引起的体重减轻水平，RND3 mRNA与脂肪细胞大小和胰岛素抵抗的替代指标（HOMA2-IR和循环甘油三酸酯/高密度脂蛋白胆固醇（TAG / HDL-C）比率）呈正相关。通过筛选分化后的人类脂肪细胞中siRNA介导的RND3敲除后RND3依赖的基因表达，我们发现炎症基因的下调和与脂肪细胞脂解和胰岛素信号转导相关的基因的上调。用肿瘤坏死因子α（TNFα），脂多糖（LPS），低氧或cAMP类似物治疗脂肪细胞可使RND3 mRNA水平提高1.5-2倍。在原代人类脂肪细胞中的功能测定证实，RND3敲低可减少cAMP和异丙肾上腺素诱导的脂解作用，而脂解作用是通过用ROCK抑制剂处理细胞来模拟的。可以通过降低甘油三酸酯脂肪酶（ATGL）和磷酸化激素敏感性脂肪酶（HSL）的蛋白质表达来部分解释这种作用。结论我们在这里发现了肥胖RND3在肥胖和胰岛素抵抗中的新型差异表达，这可能至少部分取决于RND3对脂肪细胞脂解的因果关系。