P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance

Abstract

OBJECTIVE-An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue. RESEARCH DESIGN AND METHODS-We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1 Ϫ/Ϫ ) mice compared with wild-type (WT) mice fed HFD.RESULTS-DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1 Ϫ/Ϫ mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1 Ϫ/Ϫ mice compared with WT mice fed HFD.CONCLUSIONS-These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance.

Immunity as a link between obesity and insulin resistance

“…Moreover, both acute and chronic systemic infusion of MCP-1 induces insulin resistance in rodents (Tateya et al, 2010). In agreement with these findings, Ccr2 deficient mice exhibit low ATM numbers (Weisberg et al, 2006), while PSGL-1 knockout mice are protected from high-fat diet-induced adipose inflammation (Sato et al, 2011). In contrast, MIP-1a-deficient mice are not protected against high-fat diet induced macrophage infiltration into adipose tissue (Surmi et al, 2010).…”

“…First, adipose specific overexpression of proinflammatory cytokines such as MCP-1 or Agt induces whole-body insulin resistance (Kalupahana et al, in press;Kanda et al, 2006). Second, neutralization or knock down of inflammatory mediators such as TNF-a, MCP-1, Ccr-2 and PSGL-1 protects rodents from high-fat diet-induced insulin resistance (Hotamisligil et al, 1993;Kanda et al, 2006;Sato et al, 2011;Weisberg et al, 2006). Finally, overexpression of anti-inflammatory adipokines such as adiponectin protects rodents from HF diet-induced insulin resistance (Luo et al, 2010).…”

“…Adipose tissue from obese animals expresses high levels of chemokines such as MCP-1, macrophage inflammatory protein (MIP)-1a and regulated upon activation, normal T-cell expressed and secreted (RANTES), chemokine receptors such as Ccr2 and Ccr5 (Xu et al, 2003) and adhesion molecules such as P-selectin glycoprotein ligand (PSGL)-1 (Sato et al, 2011). The expression of these chemokines, chemokine receptors and adhesion molecules play a major role in recruitment of macrophages to adipose tissue in obesity.…”

Defining macrophage phenotype and function in adipose tissue

“…A subsequent study has reported that endothelial cells are in a more proinflammatory state in visceral compared with subcutaneous human adipose tissue [34], which could favor monocyte recruitment into visceral fat. To clarify the adhesion pathways that dictate monocyte infiltration into adipose tissue, adhesion molecule gene expression profiles have been examined in obese mice [35]. Among others, P-selectin and its monocyte ligand, P-selectin glycoprotein ligand-1, are increased in adipose tissue of genetically and DIO mice, and in the latter, Psgl1 gene deletion markedly reduces macrophage accumulation.…”

β3-Adrenergic Receptor Stimulation Induces E-Selectin-mediated Adipose Tissue Inflammation

“…3). Two groups recently demonstrated that P-selectin-mediated interactions are necessary for obesityinduced insulin resistance and glucose intolerance (15,16). However, no studies have been performed to determine whether E-selectin plays a role in this process.…”