Increased oxidative stress precedes the onset of high-fat diet–induced insulin resistance and obesity

Abstract

Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c–related fatty acid synthesis and peroxisome proliferator–activated receptor α–related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor–α and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance.

Introduction

Insulin resistance and obesity are generally brought about by an excessive nutrient condition attributable to an imbalance among energy intake, expenditure, and storage. Importantly, liver and adipose tissue jointly participate in maintaining glucose and lipid homeostasis through the secretion of various humoral factors and/or neural networks [1], [2], [3]. Previous studies have validated the presence of molecular signatures typical of the liver and adipose tissue in mouse models of obesity [4] and in mice fed a high-fat diet (HFD) [5]. It is believed that perturbations in these “intertissue communications” may be involved in the development of insulin resistance, obesity, and other features of metabolic syndrome [6]. It remains unclear, however, which factors alter communication among tissues and impair the ability of tissues to adapt to changing metabolic states.

To determine which initial events trigger the development of HFD-induced insulin resistance and obesity, we globally analyzed the biological pathways that are coordinately altered in both the liver and adipose tissue of mice fed an HFD. This was accomplished through the use of microarray and quantitative real-time polymerase chain reaction (PCR) analyses. We found that oxidative stress pathways, which are regulated through the balance of reactive oxygen species (ROS) production and antioxidant enzyme activity [7], are up-regulated in both tissues before the onset of insulin resistance and obesity induced by an HFD.