Yoshinaga Ishibashi

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.

Hypoxia-inducible factor-1α suppresses the expression of macrophage scavenger receptor 1

Macrophages are distributed in all peripheral tissues and play a critical role in the first line of the innate immune defenses against bacterial infection by phagocytosis of bacterial pathogens through the macrophage scavenger receptor 1 (MSR1). Within tissues, the partial pressure of oxygen (pO2) decreases depending on the distance of cells from the closest O2-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO2. On the other hand, hypoxia-inducible factor (HIF)-1α is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1α on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O2 or treatment with the hypoxia-mimetic agent cobalt chloride (CoCl2) significantly suppressed the expression of MSR1 mRNA, accompanied by a markedly increase in levels of nuclear HIF-1α protein. The overexpression of HIF-1α in RAW264 cells suppressed the expression of MSR1 mRNA and protein, transcriptional activity of the MSR1 gene, and phagocytic capacity against the Gram-positive bacteria Listeria monocytogenes. The suppression of MSR1 mRNA by hypoxia or CoCl2 was inhibited by YC-1, an inhibitor of HIF-1α, or by the depletion of HIF-1α expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HIF-1α.

Higher levels of ATGL are associated with exercise-induced enhancement of lipolysis in rat epididymal adipocytes

Background In adipose cells, adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte triacylglyceride hydrolysis, thereby regulating both basal and hormone-stimulated lipolysis. However, little is known about the molecular mechanism(s) underlying habitual exercise-induced adaptive modulation of ATGL in white adipocytes via alteration in transcription regulator and lipolytic cofactors. Methodology/Principal Results Male Wistar rats were randomly divided into 2 groups a sedentary control group (CG) and a habitual exercise group (EG). The EG was subjected to running on a treadmill set at 5 days per week for 9 weeks. The CG was not subjected to running on a treadmill. In the EG, levels of ATGL mRNA and protein were elevated with a significant increase in lipolysis compared with the CG, accompanied by a significant increase in associations of CGI-58 with ATGL protein. Under these conditions, an upregulation of peroxisome proliferation-activated receptorg-2 (PPARg-2) was observed. In the EG, the addition of rosiglitazone further significantly increased the levels of ATGL protein compared with the CG. However, attenuated levels of the ATGL protein in adipocytes were obtained by the addition of insulin, which is known to inhibit the expression of ATGL, in both types of groups. Actually, levels of plasma insulin were significantly reduced in the EG compared with the CG. Conclusions These data suggest that elevated levels of ATGL are involved in the exercise-induced enhancement of lipolysis in primary adipocytes. The exact mechanism(s) underlying this phenomenon is associated, at least in part, with upregulated transcriptional activation of PPARg-2. In addition, exercise-induced lower circulation levels of insulin also correlate with habitual exercise-induced higher levels of ATGL in primary adipocytes.

Direct and Indirect Suppression of Interleukin-6 Gene Expression in Murine Macrophages by Nuclear Orphan Receptor REV-ERBα

It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERBα plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBα in the regulation of interleukin-6 (il6) gene expression in murine macrophages. REV-ERBα agonists, or overexpression of rev-erb α in the murine macrophage cell line RAW264 cells, suppressed the induction of il6 mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erb α overexpression decreased LPS-stimulated nuclear factor κB (NFκB) activation in RAW264 cells. We showed that REV-ERBα represses il6 expression not only indirectly through an NFκB binding motif but also directly through a REV-ERBα binding motif in the murine il6 promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erb α increased il6 mRNA expression. These data suggest that REV-ERBα regulates the inflammatory response of macrophages through the suppression of il6 expression. REV-ERBα may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.

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.

Involvement of leucine zipper transcription factor-like protein 1 (Lztfl1) in the attenuation of cognitive impairment by exercise training

It is well known that exercise prevents and reduces cognitive impairment. In the present study, we focused on exercise training as a tool to prevent cognitive impairment, and searched for novel molecules that may relate to the prevention of cognitive impairment in the hippocampus. Two-month-old senescence-accelerated mouse prone-8 (SAMP8) mice were subjected to voluntary exercise training by running on a wheel for 4 months, and were then assigned a conditioned fear memory test. Moreover, various mRNA levels in the hippocampus were examined by DNA array analysis and real-time PCR. Contextual fear memory in SAMP8 control mice was significantly impaired compared with that in non-senescence mice. Exercise training definitely attenuated such cognitive impairment. The results of real-time PCR analysis that was conducted following DNA array analysis in the hippocampus revealed that, compared with SAMR8 control mice, the expression levels of leucine zipper transcription factor-like protein 1 (Lztfl1) mRNA were significantly higher in SAMP8 mice subjected to exercise training. In addition, the overexpression of Lztfl1 promoted neurite outgrowth in Neuro 2a cells. These results suggest that exercise has a preventive effect on cognitive impairment in SAMP8 mice, and that exercise-induced increase in Lztfl1 induces neurite outgrowth.

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.

Habitual exercise training acts as a physiological stimulator for constant activation of lipolytic enzymes in rat primary white adipocytes.

It is widely accepted that lipolysis in adipocytes are regulated through the enzymatic activation of both hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) via their phosphorylation events. Accumulated evidence shows that habitual exercise training (HE) enhances the lipolytic response in primary white adipocytes with changes in the subcellular localization of lipolytic molecules. However, no study has focused on the effect that HE exerts on the phosphorylation of both HSL and ATGL in primary white adipocytes. It has been shown that the translocation of HSL from the cytosol to lipid droplet surfaces requires its phosphorylation at Ser-563. In primary white adipocytes obtained from HE rats, the level of HSL and ATGL proteins was higher than that in primary white adipocytes obtained from sedentary control (SC) rats. In HE rats, the level of phosphorylated ATGL and HSL was also significantly elevated compared with that in SC rats. These differences were confirmed by Phos-tag SDS-PAGE, a technique used to measure the amount of total phosphorylated proteins. Our results suggest that HE can consistently increase the activity of both lipases, thereby enhancing the lipolysis in white fat cells. Thus, HE helps in the prevention and treatment of obesity-related diseases by enhancing the lipolytic capacity.

We have two strategies to attain healthy aging

To attain healthy and successful aging, we emphasized the importance in making the most of easily available, rather traditional ways, such as swimming, as well as in developing a new strategy, such as the ‘working‐high sleeping‐low body temperature’ strategy.