Division of Nephrology and Hypertension, Department of Medicine, UNC Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Am J Physiol Renal Physiol. 2023 Oct 1;325(4):F491-F502. doi: 10.1152/ajprenal.00113.2023. Epub 2023 Aug 17.
Obesity is a global epidemic and risk factor for the development of chronic kidney disease. Obesity induces systemic changes in metabolism, but how it affects kidney metabolism specifically is not known. Zebrafish have previously been shown to develop obesity-related kidney pathology and dysfunction when fed hypercaloric diets. To understand the direct effects of obesity on kidney metabolic function, we treated zebrafish for 8 wk with a control and an overfeeding diet. At the end of treatment, we assessed changes in kidney and fish weights and used electron microscopy to evaluate cell ultrastructure. We then performed an untargeted metabolomic analysis on the kidney tissue of fish using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry and used mummichog and gene set enrichment analysis to uncover differentially affected metabolic pathways. Kidney metabolomes differed significantly and consistently between the control and overfed diets. Among 9,593 features, we identified 235 that were significantly different ( < 0.05) between groups (125 upregulated in overfed diet, 110 downregulated). Pathway analysis demonstrated perturbations in glycolysis and fatty acid synthesis pathways, and analysis of specific metabolites points to perturbations in tryptophan metabolism. Our key findings show that diet-induced obesity leads to metabolic changes in the kidney tissue itself and implicates specific metabolic pathways, including glycolysis and tryptophan metabolism in the pathogenesis of obesity-related kidney disease, demonstrating the power of untargeted metabolomics to identify pathways of interest by directly interrogating kidney tissue. Obesity causes systemic metabolic dysfunction, but how this affects kidney metabolism is less understood. This study used ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry to analyze the kidneys of overfed zebrafish. Metabolites in the kidneys of obese zebrafish revealed perturbations in metabolic pathways including glycolysis and tryptophan metabolism. These data suggest obesity alters metabolism within the kidney, which may play an important role in obesity-related kidney dysfunction.
肥胖是一种全球性的流行疾病，也是慢性肾脏病发展的一个风险因素。肥胖会引起全身代谢变化，但具体如何影响肾脏代谢尚不清楚。以前的研究表明，喂食高热量饮食的斑马鱼会发展出与肥胖相关的肾脏病理和功能障碍。为了了解肥胖对肾脏代谢功能的直接影响，我们用对照饮食和过量饮食处理斑马鱼 8 周。在治疗结束时，我们评估了肾脏和鱼体重量的变化，并使用电子显微镜评估细胞超微结构。然后，我们使用超高效液相色谱与高分辨率质谱联用对鱼的肾脏组织进行非靶向代谢组学分析，并使用 mummichog 和基因集富集分析来揭示受影响的差异代谢途径。对照组和过量饮食组的肾脏代谢组有显著且一致的差异。在 9593 个特征中，我们鉴定出 235 个在两组间有显著差异（<0.05）（125 个在过量饮食组上调，110 个在过量饮食组下调）。通路分析表明糖酵解和脂肪酸合成途径受到干扰，特定代谢物的分析表明色氨酸代谢受到干扰。我们的主要发现表明，饮食诱导的肥胖导致肾脏组织本身的代谢变化，并暗示特定的代谢途径，包括糖酵解和色氨酸代谢，在肥胖相关肾脏疾病的发病机制中起作用，这表明非靶向代谢组学通过直接检测肾脏组织来识别感兴趣的途径的能力。肥胖会导致全身代谢功能障碍，但这如何影响肾脏代谢尚不清楚。本研究使用超高效液相色谱与高分辨率质谱联用分析了过量饮食的斑马鱼的肾脏。肥胖斑马鱼肾脏中的代谢物揭示了代谢途径的干扰，包括糖酵解和色氨酸代谢。这些数据表明肥胖改变了肾脏内的代谢，这可能在肥胖相关的肾功能障碍中起重要作用。
