P-selectin glycoprotein ligand-1 deficiency is protective against 0besity-related insulin resistance

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 1; pp. 189 - 199
• Main Authors: Sato, Chikage, Shikata, Kenichi, Hirota, Daisho, Sasaki, Motofumi, Nishishita, Shingo, Miyamoto, Satoshi, Kodera, Ryo, Ogawa, Daisuke, Tone, Atsuhito, Kataoka, Hitomi Usui, Wada, Jun, Kajitani, Nobuo, Makino, Hirofumi
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01-01-2011
• Subjects: DNA microarrays; Gene expression; Genetic aspects; Immunohistochemistry; Insulin resistance; Methods; Obesity; Physiological aspects; Prevention; Risk factors; Japan
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1894

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.sup.-/-]) 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.sup.-/-] 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.sup.-/-] 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.