MO012RESVERATROL REGULATES NUTRIENT SENSING PATHWAY AND GUT MICROBIOTA TO PREVENT THE DEVELOPMENT OF HYPERTENSION PROGRAMMED BY MATERNAL PLUS POST-WEANING HIGH-FAT CONSUMPTION

Abstract

INTRODUCTION AND AIMS: In maternal high-fructose (HF) diet rat model of programming, we found male adult offspring develop programmed hypertension. Given that multiple insults could be additive lead to developmental programming, we hypothesize that a two-hit model with maternal plus postnatal HF will increase vulnerability to developing later life hypertension. Foods can activate several nutrient sensing mechanisms to maintain energy homeostasis, including SIRT (Silent information regulator transcript), AMP-activated protein kinase (AMPK), and PPAR pathway. Also, HF consumption can induce changes in gut microbiota that results in dysbiosis, which is linked to hypertension. Hence, we intend to examine whether resveratrol (a SIRT activator) can reprogram two-hit induced programmed hypertension via regulating nutrient sensing pathway and gut microbiota. METHODS: Female Sprague-Dawley rats were assigned to receive either a normal diet (ND) or HF diet (D12331, Research Diets) for 5 weeks before mating and during gestation and lactation. The male offspring were onto either the ND or HF diet from weaning to 4 months of age, resulting in four experimental groups (maternal diet/postweaning diet; n=8-10/group): ND/ND, ND/HF, HF/ND, and HF/HF. Rats were killed at 4 months of age. Another group of HF/HF rats (n=10) were treated with 0.01% resveratrol in drinking water during pregnancy and lactation (HF/HF+R). Rat fecal samples were collected for 16s ribosomal DNA sequencing. RESULTS: Maternal plus post-weaning HF induced increases of BPs in adult offspring, which resveratrol prevented. Post-weaning diet increased BW of both ND/HF and HF/ HF animals at 4 months of age, which was prevented by maternal resveratrol treatment. HF/HF group had higher plasma Ang I and Ang II levels, and lower Ang (1-7) level compared to those in controls. Resveratrol treatment decreased plasma Ang I and Ang II levels in the HF/HF+R group vs. HF/HF group. Additionally, HF diet significantly reduced renal mRNA expression of Sirt1, Sirt4, Ppargc1a, Ppara, and Pparg in the HF/ HF group vs. control. Resveratrol therapy increased Sirt1 and Ppargc1 expression in the HF/HF+R group. Maternal and post-weaning HF both increased the Firmicutes/ Bacteroidetes ratio, a signature of gut dysbiosis. Additionally, maternal and postweaning HF increased the relative abundance of Tenericutes (∼6-fold) and Verrucomicrobia (∼40-fold), respectively. Butyrate-producing bacteria Coprococcus was in lower quantities in the HF/HF group compared to control. In contrast, lactateproducing bacteria Lactococcus was in higher quantities in the HF/HF group compared to control. CONCLUSIONS: In conclusion, maternal plus post-weaning HF consumption induced programmed hypertension, which was related to the renin-angiotensin system, nutrient sensing pathway, and gut dysbiosis. Resveratrol (a SIRT activator) can prevent HF-induced programmed hypertension in adult male offspring, which is associated with decreases of Ang I and Ang II levels in the plasma, increased Sirt1 and Ppargc1 expression in the kidney, and partially restoring gut microbiota. It is thought that by exploring the underlying mechanisms to HF-induced programmed hypertension, we might develop novel deprogramming strategy for the prevention of programmed hypertension in children exposed to high-fat intake in early life.