Data_Sheet_1_Maternal High-Sucrose Diet Affects Phenotype Outcome in Adult Male Offspring: Role of Zbtb16.docx

Overnutrition in pregnancy and lactation affects fetal and early postnatal development, which can result in metabolic disorders in adulthood. We tested a hypothesis that variation of the Zbtb16 gene, a significant energy metabolism regulator, modulates the effect of maternal high-sucrose diet (HSD) on metabolic and transcriptomic profiles of the offspring. We used the spontaneously hypertensive rat (SHR) strain and a minimal congenic rat strain SHR-Zbtb16, carrying the Zbtb16 gene allele originating from the PD/Cub rat, a metabolic syndrome model. Sixteen-week-old SHR and SHR-Zbtb16 rat dams were fed either standard diet (control groups) or a high-sucrose diet (HSD, 70% calories as sucrose) during pregnancy and 4 weeks of lactation. In dams of both strains, we observed an HSD-induced increase of cholesterol and triacylglycerol concentrations in VLDL particles and a decrease of cholesterol and triacylglycerols content in medium to very small LDL particles. In male offspring, exposure to maternal HSD substantially increased brown fat weight in both strains, decreased triglycerides in LDL particles, and impaired glucose tolerance exclusively in SHR. The transcriptome assessment revealed networks of transcripts reflecting the shifts induced by maternal HSD with major nodes including mir-126, Hsd11b1 in the brown adipose tissue, Pcsk9, Nr0b2 in the liver and Hsd11b1, Slc2a4 in white adipose tissue. In summary, maternal HSD feeding during pregnancy and lactation affected brown fat deposition and lipid metabolism in adult male offspring and induced major transcriptome shifts in liver, white, and brown adipose tissues. The Zbtb16 variation present in the SHR-Zbtb16 led to several strain-specific effects of the maternal HSD, particularly the transcriptomic profile shifts of the adult male offspring.

妊娠与哺乳期间的营养过剩会影响胎儿及产后早期发育，进而可能导致成年后出现代谢紊乱。本研究验证了一项假说：作为关键能量代谢调控因子的Zbtb16基因（Zbtb16）变异，可调节母体高蔗糖饮食（high-sucrose diet，HSD）对子代代谢与转录组谱的影响。本研究采用了自发性高血压大鼠（spontaneously hypertensive rat，SHR）品系，以及携带源自代谢综合征模型PD/Cub大鼠的Zbtb16基因等位基因的最小同类系大鼠品系SHR-Zbtb16。将16周龄的SHR与SHR-Zbtb16孕鼠分为两组，分别饲喂标准饲料（对照组）或高蔗糖饮食（HSD，热量中70%来自蔗糖），干预周期覆盖妊娠期与4周哺乳期。在两个品系的孕鼠中，均观察到HSD可使极低密度脂蛋白（very low-density lipoprotein，VLDL）颗粒中的胆固醇与三酰甘油浓度升高，同时使中等至超小低密度脂蛋白（low-density lipoprotein，LDL）颗粒中的胆固醇与三酰甘油含量降低。在雄性子代中，母体HSD暴露可使两个品系的棕色脂肪重量显著升高，降低低密度脂蛋白颗粒中的三酰甘油水平，且仅在SHR品系中引发葡萄糖耐量受损。转录组分析显示，母体HSD诱导的转录表达变化可形成特定调控网络，其核心节点包括棕色脂肪组织中的mir-126、Hsd11b1，肝脏中的Pcsk9、Nr0b2，以及白色脂肪组织中的Hsd11b1、Slc2a4。综上，妊娠与哺乳期间母体饲喂高蔗糖饮食，会影响成年雄性子代的棕色脂肪沉积与脂质代谢，并在肝脏、白色与棕色脂肪组织中引发显著的转录组表达变化。SHR-Zbtb16品系所携带的Zbtb16基因变异，可使母体HSD产生多个品系特异性效应，尤其是对成年雄性子代的转录组谱产生显著调控变化。