Inflammation and ER Stress Regulate Branched-Chain Amino Acid Uptake and Metabolism in Adipocytes
Inflammation and ER Stress Regulate Branched-Chain Amino Acid Uptake and Metabolism in Adipocytes
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DOI：
10.1210/me.2014-1275
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发表时间：
2015-03-01
影响因子：
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通讯作者：
Bernlohr, David A.
中科院分区：
文献类型：
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作者：
Burrill, Joel S.;Long, Eric K.;Bernlohr, David A.
炎症在肥胖相关的胰岛素抵抗的病理学中起关键作用，并且与巨噬细胞衍生的细胞因子对脂肪细胞能量代谢的作用，特别是线粒体支链氨基酸（BCAA）和三羧酸（TCA）途径的作用机制相关。为了解决炎症对脂肪细胞能量代谢的作用，我们使用高脂肪喂养的C57 BL/6 J小鼠和瘦对照，并测量了与BCAA和TCA循环代谢相关的基因的下调，选择性地在内脏，而不是皮下脂肪组织，棕色脂肪，肝脏或肌肉。使用3 T3-L1细胞，TNF α和其他促炎细胞因子治疗降低了与BCAA转运和氧化相关的基因的表达。与此一致，[C-14]-亮氨酸摄取和转化为甘油三酯显着减弱TNF α处理的脂肪细胞，而转化为蛋白质相对不受影响。由于炎性细胞因子导致内质网应激的诱导，我们评估了衣霉素或毒胡萝卜素处理3 T3-L1细胞的效果，并测量了BCAA/TCA循环途径中类似的下调。此外，在脂肪细胞中过表达X-box结合蛋白1的转基因小鼠在体内类似地下调BCAA和TCA代谢的基因。这些结果表明，炎症和内质网应激通过下调BCAA/TCA代谢途径减弱内脏脂肪库中的脂肪生成，并且与肥胖胰岛素抵抗状态下血清BCAA的积累与脂肪炎症相关的模型一致。
Inflammation plays a critical role in the pathology of obesity-linked insulin resistance and is mechanistically linked to the effects of macrophage-derived cytokines on adipocyte energy metabolism, particularly that of the mitochondrial branched-chain amino acid (BCAA) and tricarboxylic acid (TCA) pathways. To address the role of inflammation on energy metabolism in adipocytes, we used high fat-fed C57BL/6J mice and lean controls and measured the down-regulation of genes linked to BCAA and TCA cycle metabolism selectively in visceral but not in subcutaneous adipose tissue, brown fat, liver, or muscle. Using 3T3-L1 cells, TNF alpha, and other proinflammatory cytokine treatments reduced the expression of the genes linked to BCAA transport and oxidation. Consistent with this, [C-14]-leucine uptake and conversion to triglycerides was markedly attenuated in TNF alpha-treated adipocytes, whereas the conversion to protein was relatively unaffected. Because inflammatory cytokines lead to the induction of endoplasmic reticulum stress, we evaluated the effects of tunicamycin or thapsigargin treatment of 3T3-L1 cells and measured a similar down-regulation in the BCAA/TCA cycle pathway. Moreover, transgenic mice overexpressing X-box binding protein 1 in adipocytes similarly down-regulated genes of BCAA and TCA metabolism in vivo. These results indicate that inflammation and endoplasmic reticulum stress attenuate lipogenesis in visceral adipose depots by down-regulating the BCAA/TCA metabolism pathway and are consistent with a model whereby the accumulation of serum BCAA in the obese insulin-resistant state is linked to adipose inflammation.