Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden.
Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.
PLoS One. 2023 Feb 14;18(2):e0281705. doi: 10.1371/journal.pone.0281705. eCollection 2023.
It is known that high-fat diet (HFD) and/or diabetes may influence substrate preferences and energy demands in the heart preceding diabetic cardiomyopathy. They may also induce structural glomerular changes causing diabetic nephropathy. PET/CT has been utilized to examine uptake of energy substrates, and to study metabolic changes or shifts before onset of metabolic disorders. However, conventional PET/CT scanning of organs with relatively low uptake, such as the kidney, in small animals in vivo may render technical difficulties. To address this issue, we developed a PET/CT ex vivo protocol with radiolabeled glucose and fatty acid analouges, [18F]FDG and [18F]FTHA,to study substrate uptake in mouse kidneys. We also aimed to detect a possible energy substrate shift before onset of diabetic nephropathy. The ex vivo protocol reduced interfering background as well as interindividual variances. We found increased uptake of [18F]FDG and [18F]FTHA in kidneys after HFD, compared to kidneys from young mice on standard chow. Levels of kidney triglycerides also increased on HFD. Lipoprotein lipase (LPL) activity, the enzyme responsible for release of fatty acids from circulating lipoproteins, is normally increased in postprandial mice kidneys. After long-term HFD, we found that LPL activity was suppressed, and could therefore not explain the increased levels of stored triglycerides. Suppressed LPL activity was associated with increased expression of angiopoietin-like protein4, an inhibitor of LPL. HFD did not alter the transcriptional control of some common glucose and fatty acid transporters that may mediate uptake of [18F]FDG and [18F]FTHA. Performing PET/CT ex vivo reduced interfering background and interindividual variances. Obesity and insulin resistance induced by HFD increased the uptake of [18F]FDG and [18F]FTHA and triglyceride accumulation in mouse kidneys. Increased levels of [18F]FDG and [18F]FTHA in obese insulin resistant mice could be used clinically as an indicator of poor metabolic control, and a complementary test for incipient diabetic nephropathy.
已知高脂肪饮食（HFD）和/或糖尿病可能会影响糖尿病心肌病发生前心脏的底物偏好和能量需求。它们还可能导致肾小球结构变化，从而导致糖尿病肾病。PET/CT 已被用于检查能量底物的摄取，并研究代谢紊乱发生前的代谢变化或转移。然而，在小动物体内对器官（如肾脏）进行相对摄取量低的常规 PET/CT 扫描可能会带来技术上的困难。为了解决这个问题，我们开发了一种使用放射性标记的葡萄糖和脂肪酸类似物 [18F]FDG 和 [18F]FTHA 的 PET/CT 离体方案，以研究小鼠肾脏中的底物摄取。我们还旨在检测糖尿病肾病发生前可能的能量底物转移。离体方案减少了干扰背景和个体间差异。我们发现，与标准饮食喂养的年轻小鼠的肾脏相比，高脂肪饮食后肾脏对 [18F]FDG 和 [18F]FTHA 的摄取增加。高脂肪饮食后，肾脏中的甘油三酯水平也增加。脂蛋白脂肪酶（LPL）的活性，即负责从循环脂蛋白中释放脂肪酸的酶，在餐后小鼠肾脏中通常会增加。经过长期高脂肪饮食后，我们发现 LPL 活性受到抑制，因此不能解释储存的甘油三酯水平增加的原因。LPL 活性的抑制与血管生成素样蛋白 4（LPL 的抑制剂）的表达增加有关。HFD 并未改变一些常见的葡萄糖和脂肪酸转运体的转录控制，这些转运体可能介导 [18F]FDG 和 [18F]FTHA 的摄取。进行 PET/CT 离体可减少干扰背景和个体间差异。HFD 引起的肥胖和胰岛素抵抗增加了 [18F]FDG 和 [18F]FTHA 的摄取以及小鼠肾脏中的甘油三酯积累。肥胖和胰岛素抵抗小鼠中 [18F]FDG 和 [18F]FTHA 水平的增加可在临床上用作代谢控制不良的指标，以及糖尿病肾病早期的补充检测。
