Deficiency of Cbl-b Gene Enhances Infiltration and Activation of Macrophages in Adipose Tissue and Causes Peripheral Insulin Resistance in Mice

Abstract

OBJECTIVE-c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action. In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action. RESEARCH DESIGN AND METHODS-C57BL/6(Cbl-b ϩ/ϩ ) or Cbl-b-deficient (Cbl-b Ϫ/Ϫ ) mice were subjected to insulin and glucose tolerance tests and a hyperinsulinemic-euglycemic clamp test. Infiltration of macrophages into white adipose tissue (WAT) was assessed by immunohistochemistry and flow cytometry. We examined macrophage activation using co-cultures of 3T3-L1 adipocytes and peritoneal macrophages. RESULTS-ElderlyCbl-b Ϫ/Ϫ mice developed glucose intolerance and peripheral insulin resistance; serum insulin concentrations after a glucose challenge were always higher in elderly Cbl-b Ϫ/Ϫ mice than age-matched Cbl-b ϩ/ϩ mice. Deficiency of the Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into WAT and glucose infusion rate, whereas fatty liver was apparent in elderly Cbl-b Ϫ/Ϫ mice. Cbl-b deficiency was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-␣, interleukin-6, and monocyte chemoattractant protein (MCP)-1. Co-culture of Cbl-b Ϫ/Ϫ macrophages with 3T3-L1 adipocytes induced leptin expression and dephosphorylation of insulin receptor substrate 1, leading to impaired glucose uptake in adipocytes. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b Ϫ/Ϫ macrophages compared with Cbl-b ϩ/ϩ macrophages. Treatment with a neutralizing anti-MCP-1 antibody improved peripheral insulin resistance and macrophage infiltration into WAT in elderly Cbl-b Ϫ/Ϫ mice. O besity is a major cause of insulin resistance (1) and is considered a chronic low-grade inflammatory disease (2). Substantial evidence has accumulated in recent years that chronic infiltration and activation of macrophages in white adipose tissue (WAT) underlie the obesity-related component of these insulin-resistant states (3-5). Infiltrating macrophages secrete proinflammatory cytokines and stimulate the secretion of adipokines from adipocytes (4,5). Tumor necrosis factor (TNF)-␣ and interleukin (IL)-6 are key factors that induce insulin resistance (6,7). Leptin and adiponectin are also suggested to act as hormones that regulate insulin resistance; hyperleptinemia in obese subjects is associated with insulin resistance in tissues such as liver, WAT, and skeletal muscle (8), whereas adiponectin increases insulin sensitivity of these tissues (9). However, the molecular mechanism of macrophage activation in WAT is still unknown. CONCLUSIONS-Cbl-b is a unique ubiquitin ligase that is associated with maturation and activation of macrophages and T-cells (10,11). Expression of Cbl-b is upregulated by macrophage/monocyte differentiation of HL60 and U937 cell lines (10). Cbl-b influences CD28-dependent T-cell activation by selectively restraining T-cell receptor-mediated Vav1 activation (12)(13)(14). A recent study reported that the ...

Functional Heterogeneity of CD11c-positive Adipose Tissue Macrophages in Diet-induced Obese Mice

“…It is now generally accepted that chronic tissue inflammation is an important cause of insulin resistance in obesity (1,3,4) and that the proinflammatory tissue macrophage, particularly in adipose tissue, can be an initiating cell type in this inflammatory response (1,(7)(8)(9). In addition, we and others have shown that a specific subpopulation of macrophages, characterized by cell surface positivity for the markers F4/80, CD11b, and CD11c, accounts for the majority of the increased macrophage influx into adipose tissue (19,28).…”

“…In both humans and rodents, macrophages (M) accumulate in adipose tissue (AT) with increasing body weight (2)(3)(4), and recent evidence implicates ATMs 2 as major contributors to tissue inflammation and insulin resistance in obesity (5,6). For example, mouse models have demonstrated that ATMs can be both necessary and sufficient (1,(7)(8)(9) for the development of insulin resistance in obesity. Specifically, disabling the inflammatory pathway within macrophages by creating myeloid cell-specific knockouts of IB kinase ␤ or JNK1 protected mice from diet-induced insulin resistance (5,6).…”

An inflammatory micro-environment promotes human adipocyte apoptosis

“…In both humans and rodents, macrophages accumulate in adipose tissue with increasing body weight (Xu et al, 2003;Weisberg et al, 2003). Several rodent studies demonstrate that an increase in adipose tissue macrophages worsens insulin sensitivity (Hirasaka et al, 2007;Kamei et al, 2006). Likewise, a decrease in adipose tissue macrophages (ATM) results in a decrease in adipose tissue inflammation and inhibits obesity-induced insulin resistance (Patsouris et al, 2008).…”

Lack of Oncostatin M Receptor β Leads to Adipose Tissue Inflammation and Insulin Resistance by Switching Macrophage Phenotype

“…Several lines of evidence now converge on the notion that obesity causes low-grade chronic inflammation characterized by the recruitment of macrophages, T-cells, and neutrophils into the adipose tissue (2)(3)(4)(5). Among such inflammatory cells, the increase in adipose tissue macrophages (ATMs) 2 is associated with a further deterioration of adipose tissue inflammation and insulin sensitivity (6,7). In contrast, a decrease in ATMs in obese mice correlates with the amelioration of adipose tissue inflammation and insulin resistance (8,9).…”