Department of Physiology, University of Ulsan College of Medicine, Seoul, Korea.
Brexogen Research Center, Brexogen Inc., Seoul, Korea.
J Clin Endocrinol Metab. 2022 Feb 17;107(3):e1057-e1073. doi: 10.1210/clinem/dgab780.
The upregulation of TRIB3 (Tribbles homolog 3), a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue.
To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance.
We measured metabolic parameters and TRIB3 expression in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes.
TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired insulin-stimulated protein kinase B (AKT) phosphorylation and caused dysregulation of the transcription of genes encoding bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor-induced expression of TRB3.
Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.
TRIB3（Tribbles 同源物 3）是一种应激诱导基因编码的假激酶，其表达上调与肥胖和 2 型糖尿病患者骨骼肌和肝脏胰岛素抵抗的发生有关。然而，关于人脂肪组织中TRIB3 的表达信息很少。
研究肥胖和 2 型糖尿病患者人脂肪组织中 TRIB3 表达是否失调，以及脂肪组织中 TRIB3 的表达是否与胰岛素抵抗有关。
我们测量了肥胖（伴或不伴 2 型糖尿病）和正常体重女性腹部皮下和内脏脂肪组织中的代谢参数和 TRIB3 表达。研究了人脂肪细胞中 TRIB3 表达的调节。
肥胖和/或 2 型糖尿病患者两个脂肪部位的 TRIB3 表达均升高；此外，表达水平与胰岛素抵抗显著相关。在模拟肥胖脂肪组织微环境的条件下孵育脂肪细胞，包括增加内质网（ER）应激，诱导 TRIB3 表达。在人脂肪细胞中，TRIB3 的过表达会损害胰岛素刺激的蛋白激酶 B（AKT）磷酸化，并导致脂肪细胞释放的生物活性分子（如促炎细胞因子、脂联素和瘦素）的转录失调。胰岛素增敏剂吡格列酮降低了 TRIB3 的这两种作用和 ER 应激诱导的 TRIB3 表达。
我们的数据表明，肥胖患者脂肪组织中的 TRIB3 表达增强，并表明增加的 TRIB3 会使脂肪细胞功能失调，这可能导致胰岛素抵抗的发生。
