The Molecular Mechanism Underlying Continuous Exercise Training-Induced Adaptive Changes of Lipolysis in White Adipose Cells

Physical exercise accelerates the mobilization of free fatty acids from white adipocytes to provide fuel for energy. This happens in several tissues and helps to regulate a whole-body state of metabolism. Under these conditions, the hydrolysis of triacylglycerol (TG) that is found in white adipocytes is known to be augmented via the activation of these lipolytic events, which is referred to as the “lipolytic cascade.” Indeed, evidence has shown that the lipolytic responses in white adipocytes are upregulated by continuous exercise training (ET) through the adaptive changes in molecules that constitute the lipolytic cascade. During the past few decades, many lipolysis-related molecules have been identified. Of note, the discovery of a new lipase, known as adipose triglyceride lipase, has redefined the existing concepts of the hormone-sensitive lipase-dependent hydrolysis of TG in white adipocytes. This review outlines the alterations in the lipolytic molecules of white adipocytes that result from ET, which includes the molecular regulation of TG lipases through the lipolytic cascade

Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

Peroxisome proliferator-activated receptor c coactivator-1α (PGC-1α) promotes the expression of oxidative enzymes in skeletalmuscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associatedwith exercise-induced PGC-1α and respiratory enzymes expression and aimed to demonstrate this under the physiological level. Wesubjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression ofrespiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1α protein, but the otherwas not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1α expression and respiratoryenzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1α andbiphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions

Copy Number Variations Due to Large Genomic Deletion in X-Linked Chronic Granulomatous Disease

Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD), but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P) H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the disease based on this. We therefore analyzed genomic rearrangements in X-linked CGD using array comparative genomic hybridization analysis, revealing the extent and the types of the deletion genes. The subjects were five Japanese X-linked CGD patients estimated to have large base deletions of 1 kb or more in the CYBB gene (four male patients, one female patient) and the mothers of four of those patients. The five Japanese patients were found to range from a patient exhibiting deletions only of the CYBB gene to a female patient exhibiting an extensive DNA deletion and the DMD and CGD phenotype manifested. Of the other three patients, two exhibited CYBB, XK, and DYNLT3 gene deletions. The remaining patient exhibited both a deletion encompassing DNA subsequent to the CYBB region following intron 2 and the DYNLT3 gene and a complex copy number variation involving the insertion of an inverted duplication of a region from the centromere side of DYNLT3 into the deleted region

The Effects of Exercise Training on Obesity-Induced Dysregulated Expression of Adipokines in White Adipose Tissue

Obesity is recognized as a risk factor for lifestyle-related diseases such as type 2 diabetes and cardiovascular disease. White adipose tissue (WAT) is not only a static storage site for energy; it is also a dynamic tissue that is actively involved in metabolic reactions and produces humoral factors, such as leptin and adiponectin, which are collectively referred to as adipokines. Additionally, because there is much evidence that obesity-induced inflammatory changes in WAT, which is caused by dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein 1, contribute to the development of insulin resistance, WAT has attracted special attention as an organ that causes diabetes and other lifestyle-related diseases. Exercise training (TR) not only leads to a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the inflammation-related adipokines in WAT. Therefore, TR is widely used as a tool for preventing and improving lifestyle-related diseases. This review outlines the impact of TR on the expression and secretory response of adipokines in WAT

Exercise Training Attenuates the Dysregulated Expression of Adipokines and Oxidative Stress in White Adipose Tissue

Obesity-induced inflammatory changes in white adipose tissue (WAT), which caused dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein-1, contribute to the development of insulin resistance. Moreover, current literature reports state that WAT generates reactive oxygen species (ROS), and the enhanced production of ROS in obese WAT has been closely associated with the dysregulated expression of adipokines in WAT. Therefore, the reduction in excess WAT and oxidative stress that results from obesity is thought to be one of the important strategies in preventing and improving lifestyle-related diseases. Exercise training (TR) not only brings about a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the adipokines in WAT. Furthermore, some reports indicate that TR affects the generation of oxidative stress in WAT. This review outlines the impact of TR on the expression of inflammation-related adipokines and oxidative stress in WAT

Standardized Extract of Asparagus officinalis Stem Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages

Excessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. A standardized extract of Asparagus officinalis stem (EAS) is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of EAS on pro-inflammatory responses in S1-stimulated macrophages. Murine peritoneal exudate macrophages were co-treated with EAS and S1. Concentrations and mRNA levels of pro-inflammatory cytokines were assessed using enzyme-linked immunosorbent assay and reverse transcription and real-time polymerase chain reaction, respectively. Expression and phosphorylation levels of signaling proteins were analyzed using western blotting and fluorescence immunomicroscopy. EAS significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. EAS also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, EAS did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, EAS significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1β by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that EAS attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, EAS may be beneficial in regulating excessive inflammation in patients with COVID-19

Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation

Regular Voluntary Exercise Potentiates Interleukin-1β and Interleukin-18 Secretion by Increasing Caspase-1 Expression in Murine Macrophages

Moderate-intensity regular exercise improves proinflammatory responses of lipopolysaccharide- (LPS-) stimulated macrophages. However, intracellular events that mediate the beneficial effects of exercise were unclear. This study aimed to clarify the mechanism by which regular voluntary exercise (VE) improves proinflammatory cytokine production by macrophages challenged with LPS. Peritoneal macrophages from VE mice secreted considerably higher amounts of interleukin- (IL-) 1β and IL-18 than did cells from sedentary control (SC) mice in the presence and absence of LPS, although tumor necrosis factor-α and IL-10 secretion were comparable between both groups. The mRNA levels of these cytokines increased significantly in response to LPS; similar levels were noted in macrophages from both SC and VE mice. Moreover, LPS evoked similar levels of degradation of inhibitor of κB (IκB) α and phosphorylation of IκB kinase β, c-Jun N-terminal kinase, and p38 in macrophages from SC and VE mice. These results indicate that the increased IL-1β and IL-18 secretion in VE mice are regulated posttranscriptionally. On the other hand, macrophages from VE mice showed higher amounts of caspase-1 protein than did cells from SC mice. These results suggest that regular VE potentiates IL-1β and IL-18 secretion in LPS-challenged macrophages by increasing caspase-1 levels