Abstract
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 (Ay/a) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in Ay/a mice (Ay/aTg) prevents increased body weight, without reducing food intake. Instead, obesity resistance in Ay/aTg 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 Ay/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.
Highlights
Oxidatively-induced damage to both nuclear and mitochondrial DNA is repaired via the base-excision repair (BER) pathway, initiated by DNA glycosylases
We have previously demonstrated that mice lacking endogenous or 8oxoguanine DNA glycosylase-1 (OGG1) (Ogg1−/−) are prone to diet-induced obesity (DIO) and its sequelae, including insulin resistance, ectopic lipid accumulation in liver and skeletal muscle, gut dysbiosis, and chronic inflammation (Sampath et al, 2012b; Vartanian et al, 2017; Simon et al, 2020)
Ay/a yellow obese mice are a genetic model of obesity resulting from antagonism of the melanocortin receptor and consequent hyperphagia (Moussa and Claycombe, 1999; Tschöp and Heiman, 2001)
Summary
Oxidatively-induced damage to both nuclear and mitochondrial DNA is repaired via the base-excision repair (BER) pathway, initiated by DNA glycosylases. Enhanced expression of human OGG1 downstream of a constitutive mitochondrial targeting sequence protects mice from DIO, insulin resistance, and adipose tissue inflammation (Komakula et al, 2018). We asked the question of whether hOGG1 expression would be protective in the context of genetically-induced obesity To address this question, we transferred the gene expressing human OGG1 downstream of a constitutive mitochondrial targeting sequence (Ogg1Tg) (Wang et al, 2011; Komakula et al, 2018) into the Ay/a obese mouse (Ay/a). Data are expressed as mean ± SEM for biological replicates; statistical comparisons were carried out by student’s t-test for 2group comparisons and by two−way ANOVA for multi−group comparisons, followed by post−hoc analysis (Bonferroni) in Graph Pad Prism (version 8.2.0 for Windows, GraphPad Software, La Jolla, CA, United States)
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