Diabetes and obesity are risk factors for kidney disease. While renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57Bl/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through 13C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared to chow-fed mice. Relative to the citric acid cycle, HF-feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) while decreasing flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from non-pyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF-feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.

中文翻译：

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体内肾皮质代谢通量因高脂肪饮食而失调

糖尿病和肥胖是肾脏疾病的危险因素。虽然糖尿病患者的肾葡萄糖生成量增加，但最近的数据表明，肾脏疾病患者的糖异生能力和氧化能力下降。因此，饮食引起的胰岛素抵抗引起的代谢失调可能会使肾脏对功能丧失变得敏感。在这里，我们研究了饮食诱导的胰岛素抵抗如何扰乱体内肾皮质的线粒体代谢通量。 C57Bl/6J 小鼠通过高脂肪 (HF) 喂养产生胰岛素抵抗；在高胰岛素-正常血糖钳夹过程中，通过 13C 同位素示踪对皮质中的回补、回补和氧化代谢通量进行量化。正如预期的那样，与食物喂养的小鼠相比，高频喂养的小鼠表现出体重增加、糖异生和全身胰岛素抵抗。相对于柠檬酸循环，高频喂养增加了通过丙酮酸羧化（回补）和磷酸烯醇丙酮酸羧激酶（回补）的代谢通量，同时减少了通过皮质中丙酮酸脱氢酶复合物的通量。此外，在高频喂养的小鼠皮质中，来自非丙酮酸来源的乙酰辅酶A的相对通量显着增加，这与氧化应激标志相关。数据表明，高频喂养可以避免丙酮酸脱氢，但会增加猝倒症，这可能会在胰岛素抵抗期间支持肾糖异生；研究结果还支持肾脏氧化代谢失调导致代谢疾病的假设。