The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

中文翻译：

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新型脂肪因子 Gremlin 1 拮抗胰岛素作用并在 2 型糖尿病和 NAFLD/NASH 中增加

BMP2/4 拮抗剂和新型脂肪因子 Gremlin 1 在人类脂肪细胞中高度表达，并在肥厚性肥胖中增加。作为分泌型拮抗剂，它抑制 BMP2/4 对脂肪前体细胞定型/分化的影响。我们检测了胰岛素关键靶组织中 Gremlin 1 的 mRNA 水平，还测量了几个仔细表型的人类队列中的组织和血清水平。Gremlin 1 在脂肪组织中的表达较高，在内脏中高于皮下组织，在肥胖中增加，在 2 型糖尿病 (T2D) 中进一步增加。在肝脏活组织检查中观察到类似的高表达，但在骨骼肌中的表达要低得多。肥胖患者的血清水平升高，但在 T2D 患者中最为突出。脂肪组织和肝脏中的转录激活以及血清水平与体内胰岛素抵抗的标志物（正常血糖钳夹和胰岛素抵抗的 HOMA）以及非酒精性脂肪性肝病 (NAFLD) 和非酒精性脂肪性肝炎 (NASH) 的存在密切相关. 我们还发现 Gremlin 1 可以拮抗人原代脂肪细胞、骨骼肌和肝细胞中的胰岛素信号传导和作用。因此，Gremlin 1 是一种新型的分泌型胰岛素拮抗剂和生物标志物，也是肥胖症及其并发症 T2D 和 NAFLD/NASH 的潜在治疗靶点。我们还发现 Gremlin 1 可以拮抗人原代脂肪细胞、骨骼肌和肝细胞中的胰岛素信号传导和作用。因此，Gremlin 1 是一种新型的分泌型胰岛素拮抗剂和生物标志物，也是肥胖症及其并发症 T2D 和 NAFLD/NASH 的潜在治疗靶点。我们还发现 Gremlin 1 可以拮抗人原代脂肪细胞、骨骼肌和肝细胞中的胰岛素信号传导和作用。因此，Gremlin 1 是一种新型的分泌型胰岛素拮抗剂和生物标志物，也是肥胖症及其并发症 T2D 和 NAFLD/NASH 的潜在治疗靶点。