Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content

Obesity and related metabolic disorders are pressing public health concerns, raising the risk for a multitude of chronic diseases. Obesity is multi-factorial disease, with both diet and lifestyle, as well as genetic and developmental factors leading to alterations in energy balance. In this regard, a novel role for DNA repair glycosylases in modulating risk for obesity has been previously established. Global deletion of either of two different glycosylases with varying substrate specificities, Nei-like endonuclease 1 (NEIL1) or 8-oxoguanine DNA glycosylase-1 (OGG1), both predispose mice to diet-induced obesity (DIO). Conversely, enhanced expression of the human OGG1 gene renders mice resistant to obesity and adiposity. This resistance to DIO is mediated through increases in whole body energy expenditure and increased respiration in adipose tissue. Here, we report that hOGG1 expression also confers resistance to genetically-induced obesity. While Agouti obese (A(y)/a) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in A(y)/a mice (A(y)/a(Tg)) prevents increased body weight, without reducing food intake. Instead, obesity resistance in A(y)/a(Tg) mice is accompanied by increased whole body energy expenditure and tissue mitochondrial content. We also report for the first time that OGG1-mediated obesity resistance in both the A(y)/a model and DIO model requires maternal transmission of the hOGG1 transgene. Maternal, but not paternal, transmission of the hOGG1 transgene is associated with obesity resistance and increased mitochondrial content in adipose tissue. These data demonstrate a critical role for OGG1 in modulating energy balance through changes in adipose tissue function. They also demonstrate the importance of OGG1 in modulating developmental programming of mitochondrial content and quality, thereby determining metabolic outcomes in offspring.

Automated summary

Obesity is a multifactorial disease influenced by diet, lifestyle, genetics, and development. DNA repair glycosylases, particularly OGG1, play a critical role in modulating the risk for obesity. Enhanced expression of hOGG1 has been shown to increase resistance to obesity in both genetically-induced and diet-induced models, with maternal transmission of the transgene being essential for this effect. The resistance to obesity mediated by OGG1 is associated with changes in energy balance, whole body energy expenditure, and mitochondrial content in adipose tissue.