OR15-05 Maternal Obesogenic Diet Exposure Leads To Transgenerational Worsening Of Offspring NAFLD In Male Mice

Disclosure: H. Hinrichs: None. S.J. Ballentine: None. M.D. Thompson: None. Background: The Developmental Origins of Health and Disease (DOHaD) hypothesis states that development of chronic disease is impacted by early life or in utero exposures. Recent studies have found that exposure to maternal obesity/obesogenic diet increases the susceptibility of offspring to non-alcoholic fatty liver disease (NAFLD). We have shown that maternal obesogenic diet exposure (MODE) in mice leads to worse NAFLD progression to fibrosis in first generation offspring with associated changes in the microbiome. Evidence indicates that some developmentally programmed phenotypes are passed transgenerationally or to the third generation of offspring. The goal of the current study was to evaluate if MODE-induced programming of worse NAFLD progression is passed transgenerationally. Methods: F0 Female mice were fed chow (CON) or high fat-fructose-cholesterol (HFFC) diet for 6 weeks and bred with lean males. F1 and F2 females were fed chow diet and mated with chow-fed males to yield an F3 generation where only the F0 female was fed HFFC diet. F3 male offspring were weaned to HFFC diet for 7 weeks to induce progressive NAFLD. Liver was collected for histopathologic analysis. NAFLD activity scoring (NAS) was performed by a pathologist blinded to group. Results: F3 HFFC offspring had decreased liver weight and liver weight/body weight ratio compared to F3 CON offspring. F3 HFFC offspring had increased hepatic free fatty acids, but no difference in hepatic triglycerides and cholesterol. Mac-2 and CD45 staining was increased in F3 HFFC offspring. Sirius red staining for collagen was also increased in F3 HFFC offspring. NAS scoring confirmed histologic finding showing an increased frequency of higher inflammation and total NAS scores in F3 HFFC offspring. Fibrosis scores were also higher in F3 HFFC offspring. Conclusions: MODE leads to transgenerational transmission of worse NAFLD progression in male offspring. This suggests a role for an epigenetic mechanism involved in developmental programming of NAFLD. Future studies will focus on the mechanisms of this transgenerational event. Presentation: Friday, June 16, 2023