Subcutaneous adipose tissue macrophage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-κB stress pathway

Abstract

Objective: To examine in obese young adults the influence of ethnicity and subcutaneous adipose tissue (SAT) inflammation on hepatic fat fraction (HFF), visceral adipose tissue (VAT) deposition, insulin sensitivity (SI), β-cell function, and SAT gene expression.

Research design and methods: SAT biopsies were obtained from 36 obese young adults (20 Hispanics, 16 African Americans) to measure crown-like structures (CLS), reflecting SAT inflammation. SAT, VAT, and HFF were measured by magnetic resonance imaging, and SI and β-cell function (disposition index [DI]) were measured by intravenous glucose tolerance test. SAT gene expression was assessed using Illumina microarrays.

Results: Participants with CLS in SAT (n = 16) were similar to those without CLS in terms of ethnicity, sex, and total body fat. Individuals with CLS had greater VAT (3.7 ± 1.3 vs. 2.6 ± 1.6 L; P = 0.04), HFF (9.9 ± 7.3 vs. 5.8 ± 4.4%; P = 0.03), tumor necrosis factor-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), fasting insulin (20.9 ± 10.6 vs. 9.7 ± 6.6 mU/mL; P < 0.001) and glucose (94.4 ± 9.3 vs. 86.8 ± 5.3 mg/dL; P = 0.005), and lower DI (1,559 ± 984 vs. 2,024 ± 829 × 10(-4) min(-1); P = 0.03). Individuals with CLS in SAT exhibited upregulation of matrix metalloproteinase-9 and monocyte antigen CD14 genes, as well as several other genes belonging to the nuclear factor-κB (NF-κB) stress pathway.

Conclusions: Adipose tissue inflammation was equally distributed between sexes and ethnicities. It was associated with partitioning of fat toward VAT and the liver and altered β-cell function, independent of total adiposity. Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

Trial registration: ClinicalTrials.gov NCT00697580.

FIG. 1.

Fasting insulin (A), TNF-α concentrations (B), VAT volume (C), and HFF (D) stratified by adipose tissue CLS status. All P values < 0.05.

FIG. 2.

Identification of CD11c+ macrophages (arrows) in CLS− (A and B) and CLS+ (C and D) individuals. Note the presence of CD11c+ immunoreactivity (brown staining) only in subjects with CLS. (A high-quality digital representation of this figure is available in the online issue.)

FIG. 3.

In individuals with high macrophage aggregation around dead adipocytes as CLS, activation stimuli such as IL-1, lipopolysaccharide (LPS) and lipopolysaccharide binding protein (LBP), and TNF-α bind to their appropriate membrane receptors. Transduction of signal from receptors activates the NF-κB pathway, which results in transcription of several secreted molecules and downregulates insulin signaling. In adipocytes, MCP-1 recruits macrophages and MMP9 stimulates adipocyte enlargement, whereas secreted ILs and TNF-α further activate inflammatory cascades and participate to insulin resistance development. TLR, Toll-like receptor; TNFR, TNF receptor.