Abstract
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.
Highlights
Overconsumption of high-carbohydrate, high-fat foods is a dietary pattern typical for Western societies and has been gaining ground in populations that were previously used to a mostly plant-based diet
Pregnant high-sucrose diet (HSD) spontaneously hypertensive rat (SHR)-Zbtb16dams displayed a higher concentration of cholesterol in medium and small very-low-density lipoproteins (VLDL) as well as in large low-density lipoproteins (LDL) compared to HSD SHR (Figure 5)
We show that the administration of HSD to pregnant rat dams significantly affects their metabolic profiles but, to a lesser extent, the metabolic and transcriptomic profiles of their inbred offspring
Summary
Overconsumption of high-carbohydrate, high-fat foods is a dietary pattern typical for Western societies and has been gaining ground in populations that were previously used to a mostly plant-based diet. It has been linked to the development of obesity, dyslipidemia, and type 2 diabetes (Softic et al, 2017), the components of metabolic syndrome (Alberti et al, 2009). Genomewide association studies have identified numerous DNA variants contributing to the genetic architecture of type 2 diabetes, dyslipidemia, or obesity, the explanation of the increase in their prevalence is still incomplete (Barroso and McCarthy, 2019). One of the genes potentially interconnecting all major components of the metabolic syndrome is zinc finger and BTB domain containing 16 (ZBTB16) transcription factor (Seda et al, 2017). We hypothesized that maternal HSD intake during pregnancy and lactation would program the offspring to develop metabolic alterations in adulthood and that these effects may be, to a certain extent, modified by genetic variation in Zbtb. We used two inbred rat strains: the spontaneously hypertensive rat (SHR), widely used model of essential hypertension prone to develop lipid and glucose metabolism disturbances (Pravenec et al, 2014), and the newly derived minimal congenic strain SHR-Zbtb differing from SHR by a 254 kb differential segment of rat chromosome 8 containing only a mutated variant of Zbtb gene of the PD/Cub strain origin (Liska et al, 2009)
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