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World J Diabetes. Mar 15, 2017; 8(3): 97-103
Published online Mar 15, 2017. doi: 10.4239/wjd.v8.i3.97
Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance
Tomoki Abe, Katsuya Hirasaka, Takeshi Nikawa
Tomoki Abe, Takeshi Nikawa, Department of Nutritional Physiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
Katsuya Hirasaka, Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, Nagasaki 852-8521, Japan
Author contributions: Abe T generated the figures and wrote the manuscript; Hirasaka K and Nikawa T specified the aims of the editorial and assisted in writing the manuscript.
Supported by The Japan Society for the Promotion of Science KAKENHI (to Tomoki Abe), No. JP15K16208.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Takeshi Nikawa, MD, PhD, Professor, Department of Nutritional Physiology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. nikawa@tokushima-u.ac.jp
Telephone: +81-88-6339248 Fax: +81-88-6337086
Received: March 25, 2016
Peer-review started: March 26, 2016
First decision: May 13, 2016
Revised: December 23, 2016
Accepted: January 11, 2017
Article in press: January 13, 2017
Published online: March 15, 2017
Processing time: 349 Days and 1.2 Hours
Abstract

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.

Keywords: Casitas b-lineage lymphoma-b; Insulin resistance; Macrophage; Obesity; Toll-like receptor 4

Core tip: Obesity leads to the development of chronic inflammation and insulin resistance (IR). Adipose tissue macrophages (ATMs) play a crucial role in the development of obesity-induced IR. Therefore, ATMs are attractive therapeutic targets for IR. Recently, we demonstrated that the ubiquitin ligase Casitas b-lineage lymphoma-b (Cbl-b) negatively regulates the migration and activation of ATMs. Here, we review key aspects of Cbl-b function in the regulation of ATMs.