P-Selectin Glycoprotein Ligand-1 Deficiency Is Protective Against Obesity-Related Insulin Resistance

摘要

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 epididy-mal 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~(-1-)) 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~(-1-) 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~(-1-) 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. Diabetes 60:189-199, 2011