In utero exposure to germinated brown rice and its oryzanol-rich extract attenuated high fat diet-induced insulin resistance in F1 generation of rats

The occurrence of type 2 diabetes amongst the pediatric population is assuming pandemic proportions, and has been linked with the growing burden of obesity, which disturbs the equilibrium between insulin secretion and sensitivity leading up to insulin resistance [15]. The cause of this pandemic is multifactorial, with several studies indicating that developmental and early life environmental conditions are important variables [16]. Insulin resistance is linked to an increase in lipid accumulation around the liver and in the visceral chambers, often as a result of increased weight gain, and has been shown to correlate with lower levels of adiponectin [17]. In the present study, the GBR groups (dams and offsprings) had low insulin levels with correspondingly high adiponectin levels. Thus, despite the low birth weight observed in GBR and OE groups the offsprings were not at risk of T2D as suggested by the raised adiponectin levels, in favour of improved insulin sensitivity. Additionally, elevated adiponectin levels can promote insulin sensitivity via increasing fat oxidation leading to a reduction of intracellular triglyceride and fatty acid levels in muscle and liver, and overall body weight, similar to what we observed in the present study [18]. As such the enhancements in metabolic indices observed in this study could have been due to elevated adiponectin, in addition to the lower body weights, in both dams and offsprings that consumed GBR and GBR-derived oryzanol. The lower body weights in the offsprings in this study may not have resulted from adverse intrauterine conditions, hence the correspondingly enhanced metabolic conditions. Moreover, we have reported severally that GBR could regulate weight gain and promote weight loss [10], which in the present study may have contributed towards enhanced metabolic outcomes.

As can be recalled, GBR and oryzanol produced metabolic outcomes that favoured insulin sensitivity better than HFD feeding in the dams and offsprings. The dietary fiber present in GBR can lower glycemic index via regulating intestinal glucose absorption, while other bioactives also contribute to better glycemic control through different mechanisms [10, 19]. Oryzanol was also observed to improve glycemic control in mice fed with HFD [20]. Moreover, the metabolic outcomes due to GBR and oryzanol could also have been secondary to lowered leptin levels [21]. Furthermore, there is an inverse correlation in type 2 diabetes between serum adiponectin and 8 – Iso prostaglandin, an important marker of oxidative stress [22], in line with the results we obtained for the HFD dams and offsprings whereby adiponectin levels were low and those of 8 – Iso prostaglandin were raised. Our results ware further supported by the RBP4 levels in the treatment groups, which showed patterns consistent with improved metabolic outcomes [23]. Overall, GBR and oryzanol were able to attenuate the HFD-induced metabolic perturbations in the dams and offsprings, although GBR showed better results suggesting that the presence of multiple compounds conferred superior bioactivity.

In recent years, epigenetic regulation of gene expression has surfaced as a key contributor in the development of metabolic disorders such that unfavorable conditions during the developmental phase (in-utero or lactation) could change the developmental programming of the offspring. In line with this, fetal nutrition is now acknowledged as a crucial regulator of fetal well-being affecting developmental programming [2, 4]. The most studied epigenetic mechanisms include DNA methylation and histone modification with the former involving the methylation at 5’ position of cytosine inside a CpG dinucleotide located at the promoter regions of genes, referred to as CpG islands. Transcriptional repression and activation in these islands is linked to hyper- and hypo-methylation, respectively [4, 24]. Our results showed that a diet of GBR in dams attenuated HFD-induced hepatic global DNA methylation changes and this in turn epigenetically influenced the lower global DNA methylation observed in their offsprings in comparison with the HFD offsprings. Post translational modifications such as acetylation of H3 and H4 also have profound effects on functional activation or repression of genes [24]. Our results also showed that GBR and GBR-derived oryzanol extract modulated H3 and H4 acetylation patterns in dams and their offsprings.

We observed in general a trend in GBR dams, which suggested epigenetically-mediated effects on the offsprings. This trend was less apparent for oryzanol treatment. From our result, it seems plausible that the synergistic effects of the multiple bioactives in GBR on the dams targeting different metabolic pathways were responsible for the attenuation of the HFD-induced metabolic effects in the offsprings, independent of any influences on the EE-BW of the offsprings’ diet. This was also the possible reason why the offsprings’ of the GBR group had better outcomes compared to those of the oryzanol group, although solvent remnants may have contributed some adverse effects to the oryzanol treatment. Similarly, the influence of GBR and oryzanol on gut microbiota of the rats during pregnancy may have contributed to the differential outcomes [2]. Thus, consumption of GBR and oryzanol can be a way to modulate the risk of insulin resistance during pregnancy, the effects of which can be observed in the F1 generation.