Reactive oxygen species-dependent regulation of pyruvate dehydrogenase kinase-4 in white adipose tissue

Abstract

Reactive oxygen species (ROS) are important signaling molecules mediating the exercise-induced adaptations in skeletal muscle. Acute exercise also drives the expression of genes involved in reesterification and glyceroneogenesis in white adipose tissue (WAT), but whether ROS play any role in this effect has not been explored. We speculated that exercise-induced ROS would regulate acute exercise-induced responses in WAT. To address this question, we utilized various models to alter redox signaling in WAT. We examined basal and exercise-induced gene expression in a genetically modified mouse model of reduced mitochondrial ROS emission [mitochondrial catalase overexpression (MCAT)]. Additionally, H2O2, various antioxidants, and the β3-adrenergic receptor agonist CL316243 were used to assess gene expression in white adipose tissue culture. MCAT mice have reduced ROS emission from WAT, enlarged WAT depots and adipocytes, and greater pyruvate dehydrogenase kinase-4 ( Pdk4) gene expression. In WAT culture, H2O2 reduced glyceroneogenic gene expression. In wild-type mice, acute exercise induced dramatic but transient increases in Pdk4 and phosphoenolpyruvate carboxykinase ( Pck1) mRNA in both subcutaneous inguinal WAT and epididymal WAT depots, which was almost completely absent in MCAT mice. Furthermore, the induction of Pdk4 and Pck1 in WAT culture by CL316243 was markedly reduced in the presence of antioxidants N-acetyl-cysteine or vitamin E. Genetic and nutritional approaches that attenuate redox signaling prevent exercise- and β-agonist-induced gene expression within WAT. Combined, these data suggest that ROS represent important mediators of gene expression within WAT.

Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance

“…ROS can modulate intracellular signaling and a transient increase in ROS levels can promote adipocyte differentiation (38,43), while sustained elevation of cellular ROS levels has been linked to adipocyte lipid storage (24), also observed in microorganisms (44). Our data shows a clear positive relationship between ROS levels and lipid accumulation in contrast to a recent study in mice, where increased mitochondrial levels of the H2O2 hydrolyzing enzyme catalase were associated with reduced ROS, increased adiposity,adipocyte size and adipose glyceroneogenic and lipogenic gene expression (45). Another study also found reduced body weight with increased ROS levels in AT with aging (46).…”

Communications between Mitochondria and Endoplasmic Reticulum in the Regulation of Metabolic Homeostasis

“…Loss of Cisd2 causes metabolic defects in patients with Wolfram syn-drome by blunting mitochondrial biogenesis, adipogenesis, insulin-stimulated glucose uptake and the secretion of adiponectin [ 140 , 152 ]. In white adipose tissues, adrenergic stimulation activates PDK4 [ 153 ] which has recently been implicated in MAM formation [ 104 ].…”

Exercise and Adipose Tissue Immunity: Outrunning Inflammation

“…Indeed, inhibition of nicotinamide adenine dinucleotide phosphate oxidase‐mediated reactive oxygen species eliminates exercise‐induced protection against myocardial infarcts in rats (16) and decreases exercise‐stimulated glucose uptake in muscle (17). Conversely, mice overexpressing mitochondrial catalase have impaired exercise‐induced regulation of pyruvate dehydrogenase kinase in AT (18). These “hormetic‐like” features of exercise are likely driven by the upregulation of adaptive or counteractive signaling cascades that oppose inflammatory signaling and quickly restore cells, tissues, or organs to new homeostatic set points (e.g., exercise training adaptations).…”