Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, Germany.
Danone Nutricia Research, Utrecht, The Netherlands.
Pharmacol Res. 2022 May;179:106193. doi: 10.1016/j.phrs.2022.106193. Epub 2022 Mar 28.
Early-life diets may have a long-lasting impact on metabolic health. This study tested the hypothesis that an early-life diet with large, phospholipid-coated lipid droplets (Concept) induces sustained improvements of hepatic mitochondrial function and metabolism. Young C57BL/6j mice were fed Concept or control (CTRL) diet from postnatal day 15 (PN15) to PN42, followed by western style (WSD) or standard rodent diet (AIN) until PN98. Measurements comprised body composition, insulin resistance (HOMA-IR), tricarboxylic acid (TCA) cycle- and β-oxidation-related hepatic oxidative capacity using high-resolution respirometry, mitochondrial dynamics, mediators of insulin resistance (diacylglycerols, DAG) or ceramides) in subcellular compartments as well as systemic oxidative stress. Concept feeding increased TCA cycle-related respiration by 33% and mitochondrial fusion protein-1 by 65% at PN42 (both p 0.05). At PN98, CTRL, but not Concept, mice developed hyperinsulinemia (CTRL/AIN 0.22 ± 0.44 vs. CTRL/WSD 1.49 ± 0.53 nmol/l, p 0.05 and Concept/AIN 0.20 ± 0.38 vs. Concept/WSD 1.00 ± 0.29 nmol/l, n.s.) and insulin resistance after WSD (CTRL/AIN 107 ± 23 vs. CTRL/WSD 738 ± 284, p 0.05 and Concept/AIN 109 ± 24 vs. Concept/WSD 524 ± 157, n.s.). WSD-induced liver weight was 18% lower in adult Concept-fed mice and β-oxidation-related respiration was 69% higher (p 0.05; Concept/WSD vs. Concept/AIN) along with lower plasma lipid peroxides (CTRL/AIN 4.85 ± 0.28 vs. CTRL/WSD 5.73 ± 0.47 µmol/l, p 0.05 and Concept/AIN 4.49 ± 0.31 vs. Concept/WSD 4.42 ± 0.33 µmol/l, n.s.) and were in part protected from WSD-induced increase in hepatic cytosolic DAG C16:0/C18:1. Early-life feeding of Concept partly protected from WSD-induced insulin resistance and systemic oxidative stress, potentially via changes in specific DAG and mitochondrial function, highlighting the role of early life diets on metabolic health later in life.
早期饮食可能对代谢健康产生持久影响。本研究旨在验证下述假设，即富含大的、磷脂包裹的脂滴的早期饮食（Concept）可诱导肝线粒体功能和代谢的持续改善。从小鼠出生后第 15 天（PN15）至第 42 天（PN42），C57BL/6j 幼鼠喂食 Concept 或对照（CTRL）饮食，随后喂食西式饮食（WSD）或标准啮齿动物饮食（AIN）直至第 98 天（PN98）。测量指标包括身体成分、胰岛素抵抗（HOMA-IR）、使用高分辨率呼吸仪测量三羧酸（TCA）循环和β-氧化相关的肝氧化能力、线粒体动力学、胰岛素抵抗相关介质（二酰基甘油，DAG）或神经酰胺）在亚细胞隔室以及全身氧化应激。Concept 喂养在 PN42 时使 TCA 循环相关呼吸增加 33%，并使线粒体融合蛋白-1增加 65%（均 p<0.05）。在 PN98 时，仅 CTRL 而非 Concept 组在 WSD 后出现高胰岛素血症（CTRL/AIN 0.22±0.44 与 CTRL/WSD 1.49±0.53 nmol/l，p<0.05；以及 Concept/AIN 0.20±0.38 与 Concept/WSD 1.00±0.29 nmol/l，无统计学差异）和胰岛素抵抗（CTRL/AIN 107±23 与 CTRL/WSD 738±284，p<0.05；以及 Concept/AIN 109±24 与 Concept/WSD 524±157，无统计学差异）。Concept 喂养的 WSD 诱导的肝重降低 18%，β-氧化相关呼吸增加 69%（p<0.05；Concept/WSD 与 Concept/AIN 相比），同时血浆脂质过氧化物降低（CTRL/AIN 4.85±0.28 与 CTRL/WSD 5.73±0.47 µmol/l，p<0.05；以及 Concept/AIN 4.49±0.31 与 Concept/WSD 4.42±0.33 µmol/l，无统计学差异），并且在一定程度上可防止 WSD 诱导的肝胞质 DAG C16:0/C18:1 增加。Concept 的早期喂养部分预防了 WSD 诱导的胰岛素抵抗和全身氧化应激，可能是通过特定的 DAG 和线粒体功能的变化，强调了早期饮食对生命后期代谢健康的影响。
