Cbl-b ケッソン ニ ヨル マクロファージ ノ カッセイカ オ カイシタ タイトウノウ イジョウ

Obesity is a major cause of insulin resistance and is considered a chronic low-grade inflammatory disease. Substantial evidence has accumulated in recent years that chronic infiltration and activation of macrophages in white adipose tissue underlie the obesity-related component of these insulin resistant states. In the present study, we examined the role of Cbl-b, ubiquitin ligase, in insulin action. Elderly Cbl-b-deficient mice（Cbl-b－/－mice）developed glucose intolerance and peripheral insulin resistance. Deficiency of Cbl-b gene was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemoattractant protein-1. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b－/－macrophages, compared with wild type macrophages, suggesting that Cbl-b deficiency induces macrophage activation. Our results suggest that Cbl-b is a negative regulator of macrophage activation, and that macrophage activation by Cbl-b deficiency, at least in part, contributes to the peripheral insulin resistance and glucose intolerance

Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice

We have previously shown that osteoactivin, a type I membrane glycoprotein expressed in myofibers, upregulated expression of matrix metalloprotease (MMP)-3 and MMP-9 in fibroblasts infiltrated denervated skeletal muscle in mice. To address whether osteoactivin-mediated increase in MMPs in skeletal muscle is useful for regeneration of denervated skeletal muscle, we subjected osteoactivin-transgenic mice to long-term denervation for 70 or 90 days. Long-term denervation caused severe degeneration of myofibers and fibrosis in skeletal muscle of wild-type mice. However, overexpression of osteoactivin protected skeletal muscle from such changes. Infiltration of fibroblast-like cells and collagen deposition were sustained at low levels after long-term denervation in skeletal muscle of osteoactivin-transgenic mice. This cytoprotective effect of osteoactivin was supported by the expression of regeneration/degeneration-associated genes in the gastrocnemius muscle during denervation. Denervation significantly upregulated the expression of anti-fibrotic genes, such as glypican-1 and decorin-1, in the gastrocnemius muscle of osteoactivin-transgenic mice, compared with wild-type mice. In contrast, overexpression of osteoactivin caused a significant reduction in denervation-induced expression of elongation factor 1A-1, an indicator for the persistence of degenerated cells. Our results suggest that an osteoactivin-mediated increase in MMPs in skeletal muscle might be useful for protecting injured muscle from fibrosis, leading to full regeneration after denervation

Soy protein diet prevents hypermethioninemia caused by portacaval shunt in rats

In hepatic disorders, abnormal plasma amino acid profiles are observed. In this study, we examined whether soy protein isolate (SPI) improved plasma methionine concentration in the model animals. Portacaval shunt (PCS) increased alanine aminotransferase (ALT) activity and methionine concentration in blood of rats fed a 40% casein diet supplemented with 0.6% methionine (casein-M diet). A 40% SPI diet supplemented with 1.28% methionine (SPI-M diet), which contained the same amount of methionine as that in 40% casein-M diet, normalized plasma ALT activity and methionine level in PCS rats. These effects of a SPI diet may be due to its amino acid composition, since an amino acid mixture diet mimicking a 40% SPI-M diet was also effective to hypermethioninemia of PCS rats. To find key enzymes for the beneficial effect of soy protein, we examined effects of a 40% SPI-M or casein-M diet on the activities of three methionine-metabolizing enzymes in liver of PCS rats. A SPI-M diet stimulated only the activity of cystathionine γ-lyase, compared with a casein-M diet. A SPI diet has a preventive effect on hypermethioninemia, at least in part, by stimulating cystathionine γ-lyase activity in liver and may be used for nutritional management of liver disorders with hypermethioninemia