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Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance

World Journal of Diabetes 2017年第3期8卷 97-103页

作者： Tomoki Abe Katsuya Hirasaka takeshi nikawa Department of Nutritional Physiology Institute of Biomedical Sciences Tokushima University Graduate School Graduate School of Fisheries Science and Environmental Studies Nagasaki University

Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance(IR). Macrophages infiltrate the adipose tissue(AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4(TLR4) and induce inflammatory responses in AT macrophages(ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b(Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs.

关键词： Casitas b-lineage lymphoma-b Insulin resistance Macrophage Obesity Toll-like receptor 4

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Distinct Gene Expression Profile Distinguishes Increased Metabolic Activity in Spontaneously Hyperactive Rats While Sedentary from That Induced by Exercise

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Advances in Biological Chemistry 2018年第1期8卷 1-14页

作者： Manami Abe Yuki Matsuo Akiko Harada-Sukeno Takayuki Uchida Kanako Kitahata Chisato Tomida Katsuya Hirasaka Shigetada Teshima-Kondo Nagakatsu Harada Yutaka Nakaya Hiroshi Sakaue Reiko Nakao takeshi nikawa Departments of Nutritional Physiology Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Laboratory of Fishery Nutritional Science Graduate School of Fisheries and Environmental Sciences Nagasaki University Nagasaki Japan Department of Medical Nutrition Graduate School of Comprehensive Rehabilitation Osaka Prefecture University Osaka Japan Departments of Nutrition and Metabolism Institute of Biomedical Sciences Tokushima University Graduate School To-kushima Japan

The Spontaneously-Running Tokushima Shikoku (SPORTS) strain is an original line derived from Wistar rats, which spontaneously runs >6 km/day on wheels, and has better glucose tolerance and less fat than Wistar rats. However, the molecular mechanism that contributes to the increased metabolic activity in SPORTS rats is unknown. The present study aimed to characterize the gene expression profiles of skeletal muscles in SPORTS rats housed under sedentary (SED) conditions. We found that the expression levels of genes encoding mitochondrial respiratory chain enzymes such as ATP synthase 6 (mt-Atp6) and cytochrome c oxidase subunit 6c (Cox6c), were higher in the soleus (SOL) muscles of SED SPORTS than in SED Wistar rats. The ratio of type IIa myofibers was higher and glucose tolerance was better in SED SPORTS than in Wistar rats that were sedentary and trained daily on treadmills, respectively. We then investigated candidate genes that might contribute to the better glucose tolerance of SED SPORTS rats using DNA microarray analysis. Among 116 upregulated genes in the SOL muscles of SED SPORTS rats, only 19 were also increased in trained Wistar rats. We focused on v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (Erbb3), which was associated with glucose transport in myocytes, and found higher expression levels in the SOL muscles of SED SPORTS than in SED Wistar rats. The SOL muscles of SED SPORTS rats also contained more activity of β-hydroxyacylCoA dehydrogenase, a key enzyme of β-oxidation, indicating enhanced lipid oxidation. These findings suggest that increased metabolic activity in skeletal muscle (especially the SOL muscle) of SPORTS rats is congenital and that gene expression profiles of SPORTS rats and Trained Wistar rats are different.

关键词： Mitochondria Myofiber Type Microarray Metabolism

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