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

Lê KA, Mahurkar S, Alderete TL, Hasson RE, Adam TC, Kim JS, Beale E, Xie C, Greenberg AS, Allayee H, Goran MI - Diabetes (2011)

Bottom Line: 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.Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Medicine, Childhood Obesity Research Center, University of Southern California, Los Angeles, California, USA.

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.

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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.
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Figure 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.

Mentions: In the same participants, we subsequently assessed gene expression in SAT biopsies. Of the 23,000 known annotated genes analyzed on the Illumina Human HT-12 chip, 375 genes (∼2%) were differentially expressed between the CLS+ and CLS− groups based on a detection P value < 0.05. Table 2 shows the top 15 differentially up- and downregulated genes in CLS+ compared with CLS− individuals. Based on Gene Ontology descriptions, molecules involved in inflammatory disease, such as matrix metalloproteinase-9 (MMP9; fold change: +4.8; P = 0.0004), interferon γ-inducible protein 30 (fold change: +2.2; P = 0.003), and IL-1 receptor antagonist (fold change: +2.0; P = 0.03), were among the most upregulated genes in CLS+ subjects compared with CLS− individuals. Genes involved in response to inflammation were also upregulated, including lipopolysaccharide binding protein (fold change: +2.0; P = 0.004), TNF receptor superfamily, member 11b (fold change: +1.4; P = 0.01), MCP-1 (fold change: +1.6; P = 0.02), and monocyte antigen CD14 (fold change: +1.5; P = 0.01). By comparison, insulin receptor substrate (IRS)-1 (fold change: −1.6; P = 0.02) and IRS-2 (fold change: −1.5; P = 0.01), which play central roles in the insulin signaling cascade, were downregulated in CLS+ individuals. Importantly, the differential expression of these inflammatory and insulin signaling genes was observed in both Hispanics and African Americans. On the basis of their relevance to inflammatory pathways we selected the following genes for RT-PCR validation: CD14, MMP9, suppressor of cytokine signaling 3, and IRS-1. In agreement with our hypothesis and the microarrays results, CLS+ individuals showed upregulation of CD14 (1.7 ± 0.9 vs. 0.9 ± 0.3; P = 0.02) and MMP9 (1.3 ± 1.1 vs. 0.3 ± 0.2; P = 0.01) compared with CLS− individuals. The suppressor of cytokine signaling 3 was upregulated (1.5 ± 1.9 vs. 0.8 ± 0.5; P = 0.2) and IRS1 was downregulated in CLS+ individuals (1.0 ± 0.6 vs. 1.4 ± 1.2; P = 0.3), but these results did not reach significance. Figure 3 shows a schematic representation of the differentially expressed molecules and their functions.


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

Lê KA, Mahurkar S, Alderete TL, Hasson RE, Adam TC, Kim JS, Beale E, Xie C, Greenberg AS, Allayee H, Goran MI - Diabetes (2011)

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.
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Related In: Results  -  Collection

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Figure 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.
Mentions: In the same participants, we subsequently assessed gene expression in SAT biopsies. Of the 23,000 known annotated genes analyzed on the Illumina Human HT-12 chip, 375 genes (∼2%) were differentially expressed between the CLS+ and CLS− groups based on a detection P value < 0.05. Table 2 shows the top 15 differentially up- and downregulated genes in CLS+ compared with CLS− individuals. Based on Gene Ontology descriptions, molecules involved in inflammatory disease, such as matrix metalloproteinase-9 (MMP9; fold change: +4.8; P = 0.0004), interferon γ-inducible protein 30 (fold change: +2.2; P = 0.003), and IL-1 receptor antagonist (fold change: +2.0; P = 0.03), were among the most upregulated genes in CLS+ subjects compared with CLS− individuals. Genes involved in response to inflammation were also upregulated, including lipopolysaccharide binding protein (fold change: +2.0; P = 0.004), TNF receptor superfamily, member 11b (fold change: +1.4; P = 0.01), MCP-1 (fold change: +1.6; P = 0.02), and monocyte antigen CD14 (fold change: +1.5; P = 0.01). By comparison, insulin receptor substrate (IRS)-1 (fold change: −1.6; P = 0.02) and IRS-2 (fold change: −1.5; P = 0.01), which play central roles in the insulin signaling cascade, were downregulated in CLS+ individuals. Importantly, the differential expression of these inflammatory and insulin signaling genes was observed in both Hispanics and African Americans. On the basis of their relevance to inflammatory pathways we selected the following genes for RT-PCR validation: CD14, MMP9, suppressor of cytokine signaling 3, and IRS-1. In agreement with our hypothesis and the microarrays results, CLS+ individuals showed upregulation of CD14 (1.7 ± 0.9 vs. 0.9 ± 0.3; P = 0.02) and MMP9 (1.3 ± 1.1 vs. 0.3 ± 0.2; P = 0.01) compared with CLS− individuals. The suppressor of cytokine signaling 3 was upregulated (1.5 ± 1.9 vs. 0.8 ± 0.5; P = 0.2) and IRS1 was downregulated in CLS+ individuals (1.0 ± 0.6 vs. 1.4 ± 1.2; P = 0.3), but these results did not reach significance. Figure 3 shows a schematic representation of the differentially expressed molecules and their functions.

Bottom Line: 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.Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Medicine, Childhood Obesity Research Center, University of Southern California, Los Angeles, California, USA.

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.

Show MeSH
Related in: MedlinePlus