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


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⁻(/)⁻) 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⁻(/)⁻ 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⁻(/) ⁻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.
Sato
Chikage
C
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Japan.
Shikata
Kenichi
K
Hirota
Daisho
D
Sasaki
Motofumi
M
Nishishita
Shingo
S
Miyamoto
Satoshi
S
Kodera
Ryo
R
Ogawa
Daisuke
D
Tone
Atsuhito
A
Kataoka
Hitomi Usui
HU
Wada
Jun
J
Kajitani
Nobuo
N
Makino
Hirofumi
H
D017667:Adipocytes / Q000502:physiology; D000818:Animals; D017931:DNA Primers; D018752:Diet, Fat-Restricted; D019040:E-Selectin / Q000235:genetics; D005234:Fatty Liver / Q000517:prevention & control; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D019007:P-Selectin / Q000235:genetics; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D017931:DNA Primers; D019040:E-Selectin; D007328:Insulin; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein