Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity
Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity
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DOI：
10.1152/ajpendo.00630.2012
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发表时间：
2013-06-01
影响因子：
5.1
通讯作者：
Adams, Sean H.
中科院分区：
文献类型：
--
作者：
Lackey, Denise E.;Lynch, Christopher J.;Adams, Sean H.
血液支链氨基酸（BCAA）升高通常与胰岛素抵抗和2型糖尿病有关，这可能是由于细胞利用率降低和/或BCAA氧化不完全所致。白色脂肪组织（WAT）已被认为是全身支链氨基酸代谢的潜在参与者。我们测试了线粒体BCAA氧化检查点，支链α-酮酸脱氢酶（BCKD）复合物的表达是否在肥胖WAT中减少并受代谢信号调节。WAT BCKD蛋白（E1 α亚基）在各种肥胖模型（fa/fa大鼠、db/db小鼠、饮食诱导的肥胖小鼠）中显著降低35-50%，并且BCKD组分转录物在来自肥胖与瘦皮马印第安人的皮下（SC）脂肪细胞中显著降低。用过氧化物酶体增殖物激活受体γ激动剂处理3 T3-L1脂肪细胞或小鼠可增加WAT BCAA分解代谢酶mRNA，而不可代谢的葡萄糖类似物2-脱氧-D-葡萄糖则具有相反的作用。研究结果支持以下假设，即WAT中的次优胰岛素作用和/或干扰的代谢信号，如胰岛素抵抗/2型糖尿病所见，可能会损害WAT BCAA的利用。然而，比较瘦型与胰岛素敏感型或胰岛素抵抗型肥胖受试者的跨组织通量研究显示，人腹部SC WAT中的BCAA摄取意外地可忽略不计。这表明，SC WAT可能不是一个重要的贡献者与胰岛素抵抗相关的血液支链氨基酸表型在过夜禁食状态。与体重匹配的健康肥胖受试者相比，患有代谢综合征的肥胖患者的网膜（但不是SC）WAT中BCAA分解代谢酶的mRNA丰度显著降低，这提高了内脏WAT有助于代谢受损个体的BCAA代谢表型的可能性。
Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain alpha-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1 alpha subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-gamma agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-D-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.