Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation[S]
Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation[S]
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DOI：
10.1194/jlr.ra119000177
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发表时间：
2020-01-01
影响因子：
6.5
通讯作者：
Kleinert, Maximillian
中科院分区：
文献类型：
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作者：
Lundsgaard, Anne-Marie;Fritzen, Andreas M.;Kleinert, Maximillian
循环中过量的FAs被认为是通过增加FAs对葡萄糖的氧化来促进葡萄糖代谢的胰岛素抵抗(IR)。因此，抑制FA氧化(FAOX)被认为可以改善IR。然而，长时间抑制FAOX可能会导致脂质堆积，从而促进脂毒性。为了了解急性和长期抑制FAOX的血糖后果，我们用肉碱棕榈酰转移酶1(CPT-1)抑制剂etomoxir(ETO)联合短期45%高脂饮食喂养的小鼠来增加FA的利用率。ETO显著增加葡萄糖氧化和外周葡萄糖处置，降低循环血糖，但这与循环FAs增加和三酰甘油在数小时内在肝脏和心脏积聚有关。每天给予ETO抑制FAOX数天可导致肝脏脂肪变性和糖耐量异常，这是ETO抑制CPT-1所特有的。伴随着全身胰岛素敏感性降低的是棕色脂肪组织(BAT)解偶联蛋白1(UCP1)蛋白含量的减少，BAT葡萄糖清除能力的降低，以及肝脏葡萄糖产量的增加。总之，这些数据表明，药物抑制FAOX不是治疗IR的可行策略，维持肝脏和BAT代谢功能需要足够量的FAOX。
Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.