The impact of NOX4 deficiency on sexually dimorphic lipid handling in HFD-challenged mice

Abstract

Dietary excess promotes metabolic dysfunction through nutrient overload. If sustained, it can impair physiological metabolic processes necessary for the proper handling of nutrients. Proper handling of nutrients depends on the capacity of an organism to properly sense, regulate, respond, and adapt to energetic demands and its energetic needs. Reactive oxygen species (ROS) are essential metabolic mediators, increasing in response to high nutrient availability and enhancing the function of proteins that regulate nutrient metabolism. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is a dynamic, pleiotropic enzyme that generates ROS in response to nutrient levels. Here we demonstrate, particularly in the liver, skeletal muscle, and bone marrow, that in conditions of nutrient overload, male mice lacking NOX4 display numerous improvements in metabolic health while females show the opposite. This work increases our understanding of factors contributing to disparities in metabolic outcomes between males and females, and underscores a role of NOX4-ROS in nutrient handling. Identifying the underlying mechanisms will aid in designing interventions to address sex-specific vulnerability and enhance resilience to nutrient overload in conditions of chronic metabolic diseases.