Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects

Abstract

Objective: Experimental studies suggest that adipose inflammation is etiologically linked to obesity-induced systemic disease. Our goal was to characterize the state of inflammation in human fat in relation to vascular function and metabolic parameters in obese individuals.

Methods and results: We collected subcutaneous abdominal fat in 77 obese subjects (BMI >or=30 kg/m(2)) and quantified adipose macrophage population using targeted immunohistochemistry. Brachial artery vasodilator function was examined using high-resolution vascular ultrasound. In 50 subjects, an inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures was associated with systemic hyperinsulinemia and insulin resistance (HOMA-IR 5.5+/-4.5 versus 2.6+/-1.9, P=0.002) and impaired endothelium-dependent flow-mediated vasodilation (8.5+/-4.4% versus 10.8+/-3.8%, P<0.05), as compared to subjects with quiescent noninflamed adipose architecture (n=27). Macrophage retention in fat was linked to upregulated tissue CD68 and tumor necrosis factor (TNF)-alpha mRNA expression in addition to increased plasma hs-CRP.

Conclusions: In a cohort of obese subjects, we demonstrate that proinflammatory changes in adipose tissue are associated with systemic arterial dysfunction and insulin resistance. These findings suggest that adipose inflammation may be linked to vascular injury and increased cardiovascular risk in obese subjects.

Figure 1

Left panel: Representative light microscopic histology of CLS+ human subcutaneous abdominal fat. Aggregates of CD68 immunoreactive macrophages (brown color) are organized in crown-like structures around individual adipocytes as a hallmark of localized chronic inflammation in adipose tissue. Right panel: CLS− adipose tissue with absence of macrophage rings.

Figure 2

(A) Fat tissue macrophage density quantified by immunohistochemistry was significantly higher in CLS+ subjects (p<0.001) which was confirmed by (B) RT-PCR CD68 gene expression (p<0.05). (C) TNF-α mRNA expression in fat quantified by RT-PCR was significantly higher in CLS+ subjects (p=0.035). Data are presented as mean ± SE.

Figure 3

Metabolic parameters stratified by fat tissue CLS status. (A) CLS+ subjects exhibited significantly higher plasma insulin concentrations (p=0.002), and (B) insulin resistance assessed by HOMA-IR (p=0.002) as compared to the CLS− group. Data are presented as mean ± SE.

Figure 4

Brachial artery flow-mediated (FMD) dilation stratified by adipose CLS status. Subjects with an inflamed fat phenotype (CLS+) had significantly worse endothelium-dependent brachial artery vasodilation (p=0.02) as compared to the CLS− group. Data are presented as mean ± SE.