Abstract
Obesity is commonly ascribed to an imbalance between caloric intake and energy expenditure - the thermodynamic, or "calories in - calories out" model. However a growing body of evidence points supports the contributions of other factors in the obesity epidemic. We previously showed that in utero exposure of pregnant F0 mice to the obesogen tributyltin (TBT) led to increased white adipose depot weight, increased hepatic fat storage and a bias of mesenchymal stem cells toward the adipogenic fate through the F3 generation. In a replicated transgenerational study, we found that exposure of F0 animals to TBT throughout pregnancy and lactation predisposed male F4 descendants of TBT-treated animals to weight gain and obesity when challenged with a higher fat diet later in life. The TBT group showed impaired ability to mobilize fat during fasting periods of fasting, accompanied by elevated serum levels of leptin. Limited fat mobilization and elevated leptin levels suggest that fat accumulation results from leptin resistance. These are hallmarks of the "thrifty phenotype" in which an individual stores more of the calories consumed and resists weight loss during times of limited food availability. Integrated methylome and transcriptome analysis from fat and liver of F4 animals revealed that ancestral TBT exposure led to changes in global DNA methylation and concomitant changes in gene expression. Our results show that ancestral, in utero exposure to TBT alters chromatin structure to modulate expression of genes important for fat storage and mobilization
