Corticotropin-Releasing Factor1 Receptors

*, 0

*, 0.05 versus siNC-EGFP; #, 0.01 versus siNC-EGFP; &, 0.05 versus siNFKB1-EGFP; and , 0.01 versus siNFKB1-EGFP (Student’s test). DISCUSSION In obese animals, adipose tissues exhibit chronic and low-grade inflammation, which is a key contributor to various metabolic disorders, such as insulin resistance, type 2 diabetes, cardiovascular disease, and atherosclerosis. interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased HTRA3 activation of the p38 Micafungin mitogen-activated protein kinase (MAPK) and NF-B pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals. INTRODUCTION Obesity is a key risk factor for metabolic diseases, including hyperlipidemia, atherosclerosis, hypertension, insulin resistance, and type 2 diabetes (1, 2). During the past few decades, the mechanisms linking obesity to metabolic diseases have been intensively investigated, and accumulating evidence suggests that the adipose tissue of the obese exhibits chronic and low-grade inflammation, which is closely associated with metabolic dysregulation (3). In obesity, adipose tissue macrophages (ATMs) produce various proinflammatory cytokines and chemokines, such as tumor necrosis factor alpha (TNF-) (4), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1), whose elevation mediates metabolic dysregulation and insulin resistance (5C8). Accordingly, MCP-1 and CCR2 (MCP-1 receptor) knockout mice are protected from insulin resistance and have a decreased number of ATMs, suggesting that proinflammatory cytokines and chemokines are essential for the recruitment of ATMs and disruption of insulin sensitivity in obesity (6, 7). Macrophages are the major effector cells that constitute the innate immune system and perform multiple roles, such as phagocytosis, secretion of cytokines and chemokines, and antigen presentation, when they recognize pathogens or cellular debris (9). These responses are mediated by the generation of reactive oxygen/reactive nitrogen species (ROS/RNS), such as superoxide (O2?), hydrogen peroxide Micafungin (H2O2), nitric oxide (NO?), and peroxynitrite (ONOO?) (10), which play a key role in killing bacteria and delivering signals as second messengers (11). ROS and RNS participate in various signaling pathways by activating and phosphorylating mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated Micafungin protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK isoforms. In addition, ROS contributes to the regulation of gene expression through modulation of several transcription factors, including NF-B (12), c-Fos, and c-Jun (13), which are responsible for the expression of proinflammatory cytokines, chemokines, and signaling components. Endogenous ROS is generated by both nonenzymatic and enzymatic reactions (14). Mitochondria are a major source of nonenzymatic ROS production (15). However, in macrophages, abundant ROS is generated by enzymatic reactions of multicomponent NADPH oxidase 2 (NOX2) (16). Upon phagocytosis and/or various stimuli, NOX2 transfers 1 electron from NADPH to oxygen to generate a superoxide anion. In addition, endogenous nitric oxide is enzymatically produced by inducible nitric oxide synthases (iNOS) through the oxidation of l-arginine in the presence of oxygen and NADPH (14). Because NOX2 and iNOS require NADPH in common, sufficient NADPH is necessary to produce cellular ROS and RNS in macrophages. Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme Micafungin of the pentose phosphate pathway (PPP), is a key enzyme Micafungin in the generation of cytosolic NADPH. G6PD participates in multiple metabolic pathways, such as reductive biosynthesis, regulation of oxidative stress, and cellular growth. We previously demonstrated that G6PD is highly expressed in the adipocytes of obese animals, and its overexpression in adipocytes impairs lipid homeostasis and adipocytokine expression, resulting in insulin resistance (17). We also showed that increased adipocyte and pancreatic -cell G6PD is closely associated with oxidative stress in the onset of metabolic disorders (18, 19). However, the functions of macrophage G6PD in pathophysiological conditions such as obesity have not been fully elucidated. Since oxidative stress is a critical factor in the regulation of macrophages’ proinflammatory roles, we hypothesized that macrophage G6PD might be a crucial enzyme that affects cellular.