158-OR: Perinatal Hypercaloric Diet Leads to Cardiometabolic Imbalance via Hypothalamic Methylation Events in Male Mice

Abstract

Cardiometabolic diseases are among the highest prevalent diseases worldwide. We have reported that perinatal maternal programming through hypercaloric diet (HCD) leads to an elevation in systolic BP and blood glucose levels exclusively in male mice offspring. These findings led us to investigate epigenetic modulations in the brain of the offspring that support the cardiometabolic phenotype. To elucidate the underlying mechanisms, we challenged the programmed offspring with postnatal HCD, speculating that it would exaggerate the cardiometabolic phenotype. C57BL6/J dams were fed on HCD or regular diet (RD) for 1 month then mated with RD-fed males. From weaning, all pups were maintained on HCD for 3 months resulting in RD-HCD and HCD-HCD groups of male mice. Results showed that HCD-HCD mice have higher systolic BP when compared to RD-HCD (125 ±1.9 vs. 115 ±2.8 mmHg) . Surprisingly, a glucose tolerance test showed that HCD-HCD mice were more glucose tolerant when compared with RD-HCD mice (AUC 29632 ±3516 vs. 604±4724, p=0.003, n=6-10/group) . Whole-genome methylation sequencing of the hypothalamus in offspring revealed differentially methylated regions (DMR) in HCD-HCD mice. Pathway analysis showed that DMR are annotated to genes involved in insulin signaling, neurotransmitter binding, and inflammatory pathways. Insulin receptor substrate (Irs1) gene exon was hypomethylated in HCD-HCD mice when compared to RD-HCD (DMR= -0.12, p=0.03) . Protein expression showed an increase in Irs1 protein fold change (FC) levels in both HCD-HCD and RD-HCD (FC=1.45 and 1.33 p=0.005, 0.03 respectively) compared to RD-fed mice. However, serine phosphorylated Irs1 (pSer307-Irs1) , an indicator for disturbed insulin signaling, showed decreased levels only in HCD-HCD mice compared to RD-HCD males (p=0.003) . We conclude that perinatal HCD programming leads to methylation events in the hypothalamus that modulate the expression of key genes regulating cardiometabolic functions. Disclosure M.Elgazzaz: None. C.Berdasco: None. E.D.Lazartigues: None. Funding American Diabetes Association (1-19-IBS-291) ;