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Myeloid heme oxygenase-1 haploinsufficiency reduces high fat diet-induced insulin resistance by affecting adipose macrophage infiltration in mice.

ABSTRACT: Increased adipose tissue macrophages contribute to obesity-induced metabolic syndrome. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory and proangiogenic activities in macrophages. However, the role of macrophage HO-1 on obesity-induced adipose inflammation and metabolic syndrome remains unclear. Here we show that high-fat diet (HFD) feeding in C57BL/6J mice induced HO-1 expression in the visceral adipose tissue, particularly the stromal vascular fraction. When the irradiated C57BL/6J mice reconstituted with wild-type or HO-1(+/-) bone marrow were fed with HFD for over 24 weeks, the HO-1(+/-) chimeras were protected from HFD-induced insulin resistance and this was associated with reduced adipose macrophage infiltration and angiogenesis, suggesting that HO-1 affects myeloid cell migration toward adipose tissue during obesity. In vivo and in vitro migration assays revealed that HO-1(+/-) macrophages exhibited an impaired migration response. Chemoattractant-induced phosphorylation of p38 and focal adhesion kinase (FAK) declined faster in HO-1(+/-) macrophages. Further experiments demonstrated that carbon monoxide and bilirubin, the byproducts derived from heme degradation by HO-1, enhanced macrophage migration by increasing phosphorylation of p38 and FAK, respectively. These data disclose a novel role of hematopoietic cell HO-1 in promoting adipose macrophage infiltration and the development of insulin resistance during obesity.

SUBMITTER: Huang JY

PROVIDER: S-EPMC3382977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:ObjectiveTo 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), ?-cell function, and SAT gene expression.Research design and methodsSAT 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 ?-cell function (disposition index [DI]) were measured by intravenous glucose tolerance test. SAT gene expression was assessed using Illumina microarrays.ResultsParticipants 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-? (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-?B (NF-?B) stress pathway.ConclusionsAdipose tissue inflammation was equally distributed between sexes and ethnicities. It was associated with partitioning of fat toward VAT and the liver and altered ?-cell function, independent of total adiposity. Several genes belonging to the NF-?B stress pathway were upregulated, suggesting stimulation of proinflammatory mediators.

| S-EPMC3198061 | biostudies-literature

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury.

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| S-EPMC5428056 | biostudies-literature

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