Center for Biomedical Sciences, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, South Korea.
Department of Biochemistry, College of Medicine, Chungbuk National University, Chungcheongbuk-do, South Korea.
Sci Rep. 2019 Sep 20;9(1):13610. doi: 10.1038/s41598-019-49578-z.
Insulin resistance is an important clinical feature of metabolic syndrome, which includes obesity and type 2 diabetes. Increased adipose energy storage in obesity promote insulin resistance and other metabolic adverse effects. To identify a new link between adipocyte and insulin resistance, we performed targeted metabolite profiling of differentiated adipocytes and studied the association between adipogenic metabolites and insulin resistance. We found a correlation between 2-aminoadipic acid (2-AAA) and adipogenic differentiation. Also, circulatory 2-AAA was positively associated with obesity-related factors (fat mass, fat percent, waist circumference, BMI, BMI z-score, triglycerides, insulin, and HOMA-IR) at baseline and after 2 years in the children cohort study. Of these factors, increased BMI z-score and HOMA-IR were the primary independent factors associated with higher 2-AAA levels, and the baseline 2-AAA level was an indicator of the BMI z-score after 2 years. To validate the relationship between 2-AAA and obesity-related factors, we analyzed changes in 2-AAA levels following obesity intervention programs in two independent studies. In both studies, changes in 2-AAA levels during the intervention period were positively correlated with changes in the BMI z-score and HOMA-IR after adjusting for confounders. Moreover, the 2-AAA levels were increased in cell and mouse models of obesity-related insulin resistance. Excess 2-AAA levels led to impaired insulin signaling in insulin-sensitive cells (liver, skeletal muscle and adipose cells) and caused abnormal gluconeogenesis. Our results demonstrate that 2-AAA is associated with adipogenesis and insulin resistance. In this regard, 2-AAA could be a potential biomarker of obesity and obesity-related metabolic disorders.
胰岛素抵抗是代谢综合征的一个重要临床特征，代谢综合征包括肥胖和 2 型糖尿病。肥胖症中脂肪组织能量储存的增加会导致胰岛素抵抗和其他代谢不良后果。为了确定脂肪细胞与胰岛素抵抗之间的新联系，我们对分化的脂肪细胞进行了靶向代谢物谱分析，并研究了脂肪生成代谢物与胰岛素抵抗之间的关联。我们发现 2-氨基己二酸（2-AAA）与脂肪生成分化之间存在相关性。此外，在儿童队列研究中，基线时和 2 年后，循环中的 2-AAA 与肥胖相关因素（脂肪量、脂肪百分比、腰围、BMI、BMI z 评分、甘油三酯、胰岛素和 HOMA-IR）呈正相关。在这些因素中，BMI z 评分增加和 HOMA-IR 是与 2-AAA 水平升高相关的主要独立因素，基线 2-AAA 水平是 2 年后 BMI z 评分的指标。为了验证 2-AAA 与肥胖相关因素之间的关系，我们在两项独立研究中分析了肥胖干预计划后 2-AAA 水平的变化。在这两项研究中，在调整混杂因素后，干预期间 2-AAA 水平的变化与 BMI z 评分和 HOMA-IR 的变化呈正相关。此外，在肥胖相关胰岛素抵抗的细胞和小鼠模型中，2-AAA 水平增加。过量的 2-AAA 水平导致胰岛素敏感细胞（肝脏、骨骼肌和脂肪细胞）中的胰岛素信号受损，并导致异常的糖异生。我们的结果表明，2-AAA 与脂肪生成和胰岛素抵抗有关。在这方面，2-AAA 可能是肥胖和肥胖相关代谢紊乱的潜在生物标志物。
