Abstract MP04: High Fat Diet Exposure Induces Epigenetic Modulation In The Brain Renin Angiotensin System

Abstract

Cardiometabolic Diseases (CMD) are one of the highest causes of morbidity and mortality worldwide. In-utero, environmental insults can program brain’s progeny through changes in gene expression level affecting cardiometabolic functions. Methylation and demethylation of DNA take place by DNA methyltransferase (DNMT) and Ten eleven translocation (TET) enzymes, respectively. Expression of renin angiotensin system (RAS) on pre-autonomic neurons in the hypothalamus is believed to play a pivotal role in sympathetic activity controlling metabolic and blood pressure (BP) homeostasis. We hypothesize that perinatal exposure to high fat high sucrose diet (HFHSD) programs the brain RAS through methylation mechanisms that lead to autonomic dysfunction and hypersensitivity to CMD. C57BL6/J dams were fed HFHSD or regular diet (RD) and mated with RD sires. After weaning, offspring were raised on RD. Three-month old progeny underwent 24 h BP recording (telemetry), measurement of fasted blood glucose (FBG), assessment of autonomic function (pharmacological) and baroreflex sensitivity (sequence method). Mice were then sacrificed, and brains harvested for quantification of mRNA levels of DNMT, TET and RAS components in the hypothalamus. HFHSD-exposed male offspring showed elevation in systolic BP (140.2 ±1.9 vs. 131.2 ±2.4 mmHg, p=0.006), heart rate (611.3 ±7.8 vs 562.5 ±7 bpm, p<0.0001) and FBG (172.7 ±6.3 vs. 142.6 ±6.3 mg/dl, p=0.018) but not females. Cardiac sympathetic activity was higher in HFHSD-exposed mice (-148 ±11.5 vs. -35.2 ±4.7 bpm, p<0.05). Surprisingly, sympathetic vascular tone was only increased in HFHSD-exposed females (-64.6 ±5.7 vs. -36.7 ±2.9 mmHg, p<0.05) while spontaneous baroreflex gain was improved in HFHSD-exposed males (5.3 ±0.7 vs. 2.6 ±0.4 msec/mmHg, p<0.05). In the brain, DNMT1, DNMT3a and TET1, 2 and 3 mRNA expression were downregulated (p<0.05) while AT 1a R and ACE2 genes were upregulated (p=0.02) in HFHSD-exposed mice. We conclude that perinatal exposure to a hypercaloric diet epigenetically programs the progeny’s brain through methylation leading to a pre-hypertensive and pre-diabetic phenotype associated with changes in the expression of RAS genes which could eventually result in increased susceptibility to CMD.