Insulin regulation of MCP-1 in human adipose tissue of obese and lean women.
CCL2 (MCP-1, monocyte chemoattractant protein 1) and CCL3 (MIP-1alpha, macrophage inflammatory protein 1alpha) are required for macrophage infiltration in adipose tissue. Insulin increases CCL2 expression in adipose tissue and in serum more in insulin-resistant obese than in insulin-sensitive lean mice, but whether this is true in humans is unknown. We compared basal expression and insulin regulation of CCL2 and CCL3 in adipose tissue and MCP-1 and MIP-1alpha in serum between insulin-resistant and insulin-sensitive human subjects. Subcutaneous adipose tissue biopsies and blood samples were obtained before and at the end of 6 h of in vivo euglycemic hyperinsulinemia (maintained by the insulin clamp technique) in 11 lean insulin-sensitive and 10 obese insulin-resistant women, and before and after a 6-h saline infusion in 8 women. Adipose tissue mRNA concentrations of monocyte/macrophage markers CD68, EMR1, ITGAM, ADAM8, chemokines CCL2 and CCL3, and housekeeping gene ribosomal protein large P0 (RPLP0) were measured by means of real-time PCR at baseline. In addition, mRNA concentrations of CCL2, CCL3, and RPLP0 were measured after insulin infusion. Levels of MCP-1 and MIP-1alpha were determined in serum, and protein concentration of MCP-1 was determined in adipose tissue at baseline and after insulin infusion. Basally, expression of the macrophage markers CD68 and EMR1 were increased in adipose tissue of insulin-resistant subjects. Insulin increased MCP-1 gene and protein expression significantly more in the insulin-resistant than in the insulin-sensitive subjects. Basally expression of CCL2 and CCL3 and expression of macrophage markers CD68 and ITGAM were significantly correlated. In serum, MCP-1 decreased significantly in insulin-sensitive but not insulin-resistant subjects. MIP-1alpha was undetectable in serum. Insulin regulation of CCL2 differs between insulin-sensitive and -resistant subjects in a direction that could exacerbate adipose tissue inflammation.
Westerbacka
Jukka
J
University of Helsinki, Department of Medicine, Division of Diabetes, Biomedicum, FIN-00029 HUCH, Helsinki, Finland. jukka.westerbacka@helsinki.fi
Cornér
Anja
A
Kolak
Maria
M
Makkonen
Janne
J
Turpeinen
Ursula
U
Hamsten
Anders
A
Fisher
Rachel M
RM
Yki-Järvinen
Hannele
H
D000273:Adipose Tissue / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D054405:Chemokine CCL3 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000032:analysis / Q000096:biosynthesis
D015415:Biomarkers; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018925:Chemokines; D018076:DNA, Complementary; D007328:Insulin; D012313:RNA