Metabolic Phenotype and Increased Adiposity in a Mouse Model of Chronic Gestational Alcohol Exposure

Abstract

Fetal Alcohol Spectrum Disorder (FASD) is the largest preventable cause of neurodevelopmental disability and recent studies suggest that prenatal alcohol exposure (PAE) also increases obesity risk at adolescence. Children with FASD exhibit hyperphagia and have inappropriate dietary intake which may contribute to increased obesity risk. We developed a mouse model of gestational binge alcohol exposure (PAE) to delineate the contributions of metabolic dysregulation, eating behavior and diet response in offspring to increased obesity risk. Pregnant C57Bl/6J females were gavaged with 3 g/kg alcohol (EtOH) daily from gestational day (GD) 12.5 to 17.5 in two half doses, two hours apart. Isocaloric maltodextrin (MD) and medium chain triglycerides (MCT) were included as nutritional controls. A sham (H2O) treatment was used to control for gavage stress. At 17 weeks, sex matched pairs from each litter were investigated for the following endpoints: obesity via dual‐energy X‐ray absorptiometry (DXA), carbohydrate metabolism using glucose tolerance testing (GTT), blood pressure and heart rate using arterial probes as well as indirect calorimetry in metabolic cages. Although lighter during lactation, EtOH pups gained significantly more weight post‐weaning than MD and MCT groups (p<0.05). EtOH offspring have increased fat mass compared with other groups at 17 weeks (p<0.05) by DXA. Male EtOH, MD, and MCT offspring exhibited increased basal glucose levels and significantly increased tolerance during GTT in comparison with H2O offspring (p<0.05) despite similar weights between groups. EtOH offspring have increased systolic blood pressure (p<0.05) and heart rate (p<0.05). In metabolic chambers, all offspring were challenged with high sugar (70%) and high fat (60%) diets. Metabolic parameters such as food intake, VO2, and respiratory exchange ratio were similar between groups, although slight differences were found in feeding behavior patterns and food intake during diet challenges between EtOH and all control groups. After a month on high fat diet, male EtOH offspring have exacerbated weight and fat mass gain (p<0.05). After a month on high fat diet, female EtOH offspring exhibit significantly increased basal glucose levels (p>0.05) and increased glucose tolerance during GTT. Taken together, these data suggest that PAE may be associated with a metabolic syndrome. Up to 1 in 3 women report drinking during pregnancy, so PAE may be a previously unrecognized factor for increased obesity risk in the context of an obesogenic environment.Support or Funding InformationAA22999. AA11085, 2T32DK007665