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

Mentions: A total of 36 obese participants with an average BMI of 35.6 ± 3.9 kg/m2 completed the study (mean age 21.2 ± 2.3 years; 55% Hispanics, 55% women). We first carried out histological analyses of adipose biopsies to determine the presence of aggregated macrophages as CLS. Mean section area was 14.0 ± 5.1 mm2; 16 participants showed presence of CLS (CLS+), whereas there were no signs of CLS in the remaining 20 participants (CLS−). In the CLS+ participants, the mean number of CLS per 400 adipocytes was 12.9 ± 17.9, with a median of 5.4 and an interquartile range of 2.4–14.2. The characteristics of the participants, stratified by CLS status, are shown in Table 1. Of note, CLS+ participants were equally distributed among men and women as well as Hispanics and African Americans (χ2 tests: P > 0.05), even after adjusting for total fat and VAT. This suggests that major differences with respect to the presence of CLS are not driven by sex or ethnicity in our study population. In the whole group, CLS+ individuals had increased 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), fasting TNF-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), and insulin concentrations (20.8 ± 2.6 vs. 9.7 ± 6.5 mU/mL; P = 0.0007), independent of sex, ethnicity, total fat, and visceral fat volume (Fig. 1). Markers of insulin resistance, including fasting glucose, fasting insulin, HOMA-IR, and HOMA-β, were also significantly higher in the CLS+ group, compared with the CLS−, and these comparisons remained significant after adjusting for covariates. DI, reflecting β-cell function, was significantly lower in the CLS+ group (1,559 ± 984 vs. 2,024 ± 829 ×10−4 min−1; P = 0.03), whereas SI, glucose effectiveness, and AIR were not significantly different (Table 1). HDL cholesterol concentrations tended to be lower in CLS+ participants (P = 0.09), but there were no differences in fasting TGs and total and LDL cholesterol concentrations. In a subset of participants, we performed further immunohistochemical studies to examine the presence of CD11c+ immunoreactivity, to detect the presence of dendritic cells. Of the six participants with CLS+, four of them showed positive CD11c immunoreactivity staining, whereas it was completely absent in all four CLS− participants (Fig. 2). CD11c+ cells are a subclass of macrophages, called dendritic cells, which have been demonstrated to be proinflammatory and linked to systemic insulin resistance (10,16).


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)

Fasting insulin (A), TNF-α concentrations (B), VAT volume (C), and HFF (D) stratified by adipose tissue CLS status. All P values < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198061&req=5

Figure 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.
Mentions: A total of 36 obese participants with an average BMI of 35.6 ± 3.9 kg/m2 completed the study (mean age 21.2 ± 2.3 years; 55% Hispanics, 55% women). We first carried out histological analyses of adipose biopsies to determine the presence of aggregated macrophages as CLS. Mean section area was 14.0 ± 5.1 mm2; 16 participants showed presence of CLS (CLS+), whereas there were no signs of CLS in the remaining 20 participants (CLS−). In the CLS+ participants, the mean number of CLS per 400 adipocytes was 12.9 ± 17.9, with a median of 5.4 and an interquartile range of 2.4–14.2. The characteristics of the participants, stratified by CLS status, are shown in Table 1. Of note, CLS+ participants were equally distributed among men and women as well as Hispanics and African Americans (χ2 tests: P > 0.05), even after adjusting for total fat and VAT. This suggests that major differences with respect to the presence of CLS are not driven by sex or ethnicity in our study population. In the whole group, CLS+ individuals had increased 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), fasting TNF-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), and insulin concentrations (20.8 ± 2.6 vs. 9.7 ± 6.5 mU/mL; P = 0.0007), independent of sex, ethnicity, total fat, and visceral fat volume (Fig. 1). Markers of insulin resistance, including fasting glucose, fasting insulin, HOMA-IR, and HOMA-β, were also significantly higher in the CLS+ group, compared with the CLS−, and these comparisons remained significant after adjusting for covariates. DI, reflecting β-cell function, was significantly lower in the CLS+ group (1,559 ± 984 vs. 2,024 ± 829 ×10−4 min−1; P = 0.03), whereas SI, glucose effectiveness, and AIR were not significantly different (Table 1). HDL cholesterol concentrations tended to be lower in CLS+ participants (P = 0.09), but there were no differences in fasting TGs and total and LDL cholesterol concentrations. In a subset of participants, we performed further immunohistochemical studies to examine the presence of CD11c+ immunoreactivity, to detect the presence of dendritic cells. Of the six participants with CLS+, four of them showed positive CD11c immunoreactivity staining, whereas it was completely absent in all four CLS− participants (Fig. 2). CD11c+ cells are a subclass of macrophages, called dendritic cells, which have been demonstrated to be proinflammatory and linked to systemic insulin resistance (10,16).

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