Department of Human Physiology, University of Oregon, Eugene, OR.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
Diabetes. 2023 Dec 1;72(12):1766-1780. doi: 10.2337/db23-0289.
Maternal consumption of a Western-style diet (mWD) during pregnancy alters fatty acid metabolism and reduces insulin sensitivity in fetal skeletal muscle. The long-term impact of these fetal adaptations and the pathways underlying disordered lipid metabolism are incompletely understood. Therefore, we tested whether a mWD chronically fed to lean, insulin-sensitive adult Japanese macaques throughout pregnancy and lactation would impact skeletal muscle oxidative capacity and lipid metabolism in adolescent offspring fed a postweaning (pw) Western-style diet (WD) or control diet (CD). Although body weight was not different, retroperitoneal fat mass and subscapular skinfold thickness were significantly higher in pwWD offspring consistent with elevated fasting insulin and glucose. Maximal complex I (CI)-dependent respiration in muscle was lower in mWD offspring in the presence of fatty acids, suggesting that mWD impacts muscle integration of lipid with nonlipid oxidation. Abundance of all five oxidative phosphorylation complexes and VDAC, but not ETF/ETFDH, were reduced with mWD, partially explaining the lower respiratory capacity with lipids. Muscle triglycerides increased with pwWD; however, the fold increase in lipid saturation, 1,2-diacylglycerides, and C18 ceramide compared between pwCD and pwWD was greatest in mWD offspring. Reductions in CI abundance and VDAC correlated with reduced markers of oxidative stress, suggesting that these reductions may be an early-life adaptation to mWD to mitigate excess reactive oxygen species. Altogether, mWD, independent of maternal obesity or insulin resistance, results in sustained metabolic reprogramming in offspring muscle despite a healthy diet intervention.
In lean, active adolescent offspring, a postweaning Western-style diet (pwWD) leads to shifts in body fat distribution that are associated with poorer insulin sensitivity. Fatty acid-linked oxidative metabolism was reduced in skeletal muscles from offspring exposed to maternal Western-style diet (mWD) even when weaned to a healthy control diet for years. Reduced oxidative phosphorylation complex I-V and VDAC1 abundance partially explain decreased skeletal muscle respiration in mWD offspring. Prior exposure to mWD results in greater fold increase with pwWD in saturated lipids and bioactive lipid molecules (i.e. ceramide and sphingomyelin) associated with insulin resistance.
怀孕期间母体摄入西式饮食（mWD）会改变脂肪酸代谢并降低胎儿骨骼肌的胰岛素敏感性。这些胎儿适应性的长期影响以及紊乱脂质代谢的途径尚不完全清楚。因此，我们测试了在怀孕期间和哺乳期通过慢性喂养 lean、胰岛素敏感的成年日本猕猴的 mWD 是否会影响在青少年后代中喂养 PW 西式饮食（WD）或对照饮食（CD）时的骨骼肌氧化能力和脂质代谢。尽管体重没有差异，但 PWWD 后代的腹膜后脂肪量和肩胛下皮褶厚度明显较高，与空腹胰岛素和葡萄糖升高一致。在存在脂肪酸的情况下，mWD 后代的肌肉中最大的复合物 I（CI）依赖性呼吸降低，这表明 mWD 影响了肌肉将脂质与非脂质氧化整合。mWD 降低了所有五个氧化磷酸化复合物和 VDAC 的丰度，但不降低 ETF/ETFDH，部分解释了与脂质相关的呼吸能力降低。肌肉甘油三酯随着 PWWD 而增加；然而，与 PWCD 相比，PWWD 中脂质饱和度、1,2-二酰甘油和 C18 神经酰胺的增加幅度最大。CI 丰度和 VDAC 的降低与氧化应激标志物的降低相关，表明这些降低可能是对 mWD 的早期生活适应，以减轻过多的活性氧。总之，尽管进行了健康饮食干预，但 mWD 独立于母体肥胖或胰岛素抵抗，导致后代肌肉持续的代谢重编程。
在 lean、活跃的青少年后代中，PWWD 导致身体脂肪分布的变化，这与较差的胰岛素敏感性有关。即使在断奶多年后接受健康对照饮食，暴露于 mWD 的后代的骨骼肌中与脂肪酸相关的氧化代谢也会降低。氧化磷酸化复合物 I-V 和 VDAC1 丰度的降低部分解释了 mWD 后代骨骼肌呼吸减少。先前暴露于 mWD 会导致 PWWD 时与胰岛素抵抗相关的饱和脂质和生物活性脂质分子（即神经酰胺和鞘磷脂）的增加幅度更大。
