Prenatal Exposure to Mild High Fat Diet Paradoxically Leads to Improvement in Cardio‐Metabolic Function in the Offspring
Authors: Mukerjee Snigdha , Zhu Yun , Zhao Jinying , Zsombok Andrea , Lazartigues Eric 
Published: November 2023

Maternal diet has a profound impact on development and physiology of the progeny. Although the influence of diet‐induced fetal programming has been assessed with regards to protein deficiency, the impact of a Western diet on epigenetic mechanisms is unknown. The classic (ACE/Ang‐II/AT1R) and compensatory (ACE2/Ang‐(1‐7)/MasR) renin angiotensin system (RAS), has been suggested to be a target of epigenetic modifications. Moreover, hypertension and metabolic disorders occur when the balance between the 2 RAS axes shifts in favor of the classical pathway. Therefore epigenetic mechanisms such as DNA methylation of genes encoding RAS components might play a critical role in the development of cardio‐metabolic diseases. We hypothesize that high fat diet consumption during pregnancy leads to epigenetic modifications within the progeny's brain RAS, promoting autonomic dysfunction and metabolic disorders. In our model, female mice were fed regular chow (RD) or 45% high fat diet and 30% sucrose solution (HFHS) from mating until weaning of the pups (~7 weeks). Offspring from both groups were then maintained on chow and studied in adulthood. DNA methylation within selected brain regions were analyzed using bisulfite sequencing. Dams on HFHS diet had increased total plasma cholesterol (HFHS: 194 ±5 vs. RD: 117 ±5 mg/dl, n=4, p<0.05). In the offspring, we found no change in body weight (HFHS: 24 ±2 vs. RD: 26 ±1 g, n=5–7) and fasting blood glucose (HFHS: 139 ±14 vs. RD: 136 ±9 mg/dl, n=5–7). Gene expression of one of the key players of the classical RAS, i.e. AT1R, was increased within the hypothalamus in the brain, of 3‐month‐old HFHS offspring (HFHS: 1.8 ±0.2 vs. RD: 1 ±0.1 fold change, n=4–5, p<0.05). However this effect disappeared in 7‐month‐old HFHS offspring. Within the brainstem, DNA methylation was significantly lower for the ACE2 gene (p<0.05) and ACE2 activity increased within the hypothalamus (HFHS: 91 ±1 vs. RD: 74 ±4 AFU/mg/min, n=3–5, p<0.05). Baseline blood pressure (BP, telemetry) was also lower in the HFHS progeny (HFHS: 97 ± 3 vs. RD: 117 ± 7 mmHg, n=4–5, p<0.05). DNA methylation was reduced for FFAR2/3, short‐chain fatty acid receptors, within the brainstem (p<0.05) and their gene expression was increased in the hypothalamus of HFHS progeny (FFAR2: HFHS: 2.7 ±0.3 vs. RD: 1±0.04, n=4–5, p<0.05; FFAR3: HFHS: 6.1±1.2 vs. RD: 1 .1±0.1 fold change, n=4–5 p<0.05). Moreover, there was a trend towards an improved glucose tolerance (AUC: HFHS: 3738 ±273.5 vs. RD: 4952 ±378.2; p=0.07) which, coupled with an increase in GLUT4 gene expression in the liver (HFHS: 2.7± 0.3 vs. RD: 1 ±0.1; p<0.05) indicated an improved glucose uptake among the HFHS progeny. Taken together, our data suggests that perinatal exposure to HFHS diet might have resulted in epigenetic modifications of the brain RAS, potentially affecting plasticity of neuronal networks leading to reduced baseline BP and improved peripheral glucose uptake in HFHS offspring.Support or Funding InformationNIH/NHLBI (HL093178)COBRE (P30GM106392)