In the Beginning: Insight into Parental Influence on Offspring Metabolic Disease Susceptibility in Mice and Humans

Abstract

The increases in type 2 diabetes (T2DM) and obesity cannot be explained solely by lifestyle and genetic factors. Recent evidence suggests alterations to the intrauterine environment as well as paternal factors may contribute to increased susceptibility. Exposure to maternal high fat diet (HFD), maternal obesity or intrauterine growth restriction (IUGR) are associated with increased inflammation and oxidative stress. To understand the role of these factors in metabolic disease susceptibility we utilized two approaches. The first was to investigate the effect of exposure to HFD supplemented with the anti-oxidant, anti-inflammatory N-acetylcysteine (NAC) in a murine model. Administration of NAC during gestation and lactation resulted in improvements in both the dam and offspring. The data suggests HFD-induced oxidative stress and inflammation play an important role in programming metabolic disease and antioxidant treatment during critical periods of development may prevent the onset or reduce the severity of metabolic disease in offspring exposed to maternal HFD.;A translational approach was taken to elucidate epigenetic changes associated with IUGR or elevated maternal pre-pregnancy BMI on DNA methylation of umbilical cord blood purified CD3+ T-lymphocytes. A global shift in hypermethylation targeted to regulatory regions of the genome and dysregulation of pathways involved with T2DM and T-cell development was observed in male IUGR offspring. In appropriate for gestational age babies born to mothers with elevated pre-pregnancy BMI, a sex-dependent dysregulation of the methylome, targeted to promoters and enhancers, imprinted genes and genes associated with T2DM and obesity was observed. These results demonstrate the utility of CD3+ T-lymphocytes as a surrogate cell to evaluate intrauterine exposures in offspring at risk for metabolic disease.;Paternal in-utero HFD exposure resulted in a sexual dimorphic response in non-exposed offspring suggesting that paternal environmental exposures, such as a high fat obesogenic diet, play a role in the developmental origins of health and disease.;Determining parental environmental factors that influence long-term health of the offspring is important in developing preventive strategies for diabetes and obesity. Our combined approach demonstrates that the intrauterine environment influences metabolic disease susceptibility and provides evidence for a causal role of oxidative stress in the development of metabolic disease.